Carboxamides as modulators of sodium channels

ABSTRACT

Compounds, and pharmaceutically acceptable salts thereof, useful as inhibitors of sodium channels are provided. Also provided are pharmaceutical compositions comprising the compounds or pharmaceutically acceptable salts and methods of using the compounds, pharmaceutically acceptable salts, and pharmaceutical compositions in the treatment of various disorders, including pain.

BACKGROUND

Pain is a protective mechanism that allows healthy animals to avoidtissue damage and to prevent further damage to injured tissue.Nonetheless there are many conditions where pain persists beyond itsusefulness, or where patients would benefit from inhibition of pain.Neuropathic pain is a form of chronic pain caused by an injury to thesensory nerves (Dieleman, J. P., et al., Incidence rates and treatmentof neuropathic pain conditions in the general population. Pain, 2008.137(3): p. 681-8). Neuropathic pain can be divided into two categories,pain caused by generalized metabolic damage to the nerve and pain causedby a discrete nerve injury. The metabolic neuropathies includepost-herpetic neuropathy, diabetic neuropathy, and drug-inducedneuropathy. Discrete nerve injury indications include post amputationpain, post-surgical nerve injury pain, and nerve entrapment injurieslike neuropathic back pain.

Voltage-gated sodium channels (Na_(V)s) are involved in pain signaling.Na_(V)s are biological mediators of electrical signaling as they mediatethe rapid upstroke of the action potential of many excitable cell types(e.g. neurons, skeletal myocytes, cardiac myocytes). The evidence forthe role of these channels in normal physiology, the pathological statesarising from mutations in sodium channel genes, preclinical work inanimal models, and the clinical pharmacology of known sodium channelmodulating agents all point to the central role of Na_(V)s in painsensation (Rush, A. M. and T. R. Cummins, Painful Research:Identification of a Small-Molecule Inhibitor that Selectively Targets Na_(V)1.8 Sodium Channels. Mol. Interv., 2007. 7(4): p. 192-5); England,S., Voltage-gated sodium channels: the search for subtype-selectiveanalgesics. Expert Opin. Investig. Drugs 17 (12), p. 1849-64 (2008);Krafte, D. S. and Bannon, A. W., Sodium channels and nociception: recentconcepts and therapeutic opportunities. Curr. Opin. Pharmacol. 8 (1), p.50-56 (2008)). Na_(V)s mediate the rapid upstroke of the actionpotential of many excitable cell types (e.g. neurons, skeletal myocytes,cardiac myocytes), and thus are involved in the initiation of signalingin those cells (Hille, Bertil, Ion Channels of Excitable Membranes,Third ed. (Sinauer Associates, Inc., Sunderland, Mass., 2001)). Becauseof the role Na_(V)s play in the initiation and propagation of neuronalsignals, antagonists that reduce Na_(V) currents can prevent or reduceneural signaling and Na_(V) channels have been considered likely targetsto reduce pain in conditions where hyper-excitability is observed(Chahine, M., Chatelier, A., Babich, O., and Krupp, J. J., Voltage-gatedsodium channels in neurological disorders. CNS Neurol. Disord. DrugTargets 7 (2), p. 144-58 (2008)). Several clinically useful analgesicshave been identified as inhibitors of Na_(V) channels. The localanesthetic drugs such as lidocaine block pain by inhibiting Na_(V)channels, and other compounds, such as carbamazepine, lamotrigine, andtricyclic antidepressants that have proven effective at reducing painhave also been suggested to act by sodium channel inhibition (Soderpalm,B., Anticonvulsants: aspects of their mechanisms of action. Eur. J. Pain6 Suppl. A, p. 3-9 (2002); Wang, G. K., Mitchell, J., and Wang, S. Y.,Block of persistent late Na⁺ currents by antidepressant sertraline andparoxetine. J. Membr. Biol. 222 (2), p. 79-90 (2008)).

The Na_(V)s form a subfamily of the voltage-gated ion channelsuper-family and comprises 9 isoforms, designated Na_(V)1.1-Na_(V)1.9.The tissue localizations of the nine isoforms vary. Na_(V)1.4 is theprimary sodium channel of skeletal muscle, and Na_(V)1.5 is primarysodium channel of cardiac myocytes. Na_(V)s 1.7, 1.8 and 1.9 areprimarily localized to the peripheral nervous system, while Na_(V)s 1.1,1.2, 1.3, and 1.6 are neuronal channels found in both the central andperipheral nervous systems. The functional behaviors of the nineisoforms are similar but distinct in the specifics of theirvoltage-dependent and kinetic behavior (Catterall, W. A., Goldin, A. L.,and Waxman, S. G., International Union of Pharmacology. XLVII.Nomenclature and structure-function relationships of voltage-gatedsodium channels. Pharmacol. Rev. 57 (4), p. 397 (2005)).

Upon their discovery, Na_(V)1.8 channels were identified as likelytargets for analgesia (Akopian, A. N., L. Sivilotti, and J. N. Wood, Atetrodotoxin-resistant voltage-gated sodium channel expressed by sensoryneurons. Nature, 1996. 379(6562): p. 257-62). Since then, Na_(V)1.8 hasbeen shown to be a carrier of the sodium current that maintains actionpotential firing in small dorsal root ganglia (DRG) neurons (Blair, N.T. and B. P. Bean, Roles oftetrodotoxin (TTX)-sensitive Na⁺ current,TTX-resistant Na⁺ current, and Ca²⁺ current in the action potentials ofnociceptive sensory neurons. J. Neurosci., 2002. 22(23): p. 10277-90).Na_(V)1.8 is involved in spontaneous firing in damaged neurons, likethose that drive neuropathic pain (Roza, C., et al., Thetetrodotoxin-resistant Na⁺ channel Na_(V)1.8 is essential for theexpression of spontaneous activity in damaged sensory axons of mice. JPhysiol., 2003. 550 (Pt 3): p. 921-6; Jarvis, M. F., et al., A-803467, apotent and selective Na_(V)1.8 sodium channel blocker, attenuatesneuropathic and inflammatory pain in the rat. Proc. Natl. Acad. Sci.USA, 2007. 104(20): p. 8520-5; Joshi, S. K., et al., Involvement of theTTX-resistant sodium channel Na_(V)1.8 in inflammatory and neuropathic,but not post-operative, pain states. Pain, 2006. 123(1-2): pp. 75-82;Lai, J., et al., Inhibition of neuropathic pain by decreased expressionof the tetrodotoxin-resistant sodium channel, Na_(V)1.8. Pain, 2002.95(1-2): p. 143-52; Dong, X. W., et al., Small interfering RNA-mediatedselective knockdown of Na_(V)1.8 tetrodotoxin-resistant sodium channelreverses mechanical allodynia in neuropathic rats. Neuroscience, 2007.146(2): p. 812-21; Huang, H. L., et al., Proteomic profiling of neuromasreveals alterations in protein composition and local protein synthesisin hyper-excitable nerves. Mol. Pain, 2008. 4: p. 33; Black, J. A., etal., Multiple sodium channel isoforms and mitogen-activated proteinkinases are present in painful human neuromas. Ann. Neurol., 2008.64(6): p. 644-53; Coward, K., et al., Immunolocalization of SNS/PN3 andNaN/SNS2 sodium channels in human pain states. Pain, 2000. 85(1-2): p.41-50; Yiangou, Y., et al., SNS/PN3 and SNS2/NaN sodium channel-likeimmunoreactivity in human adult and neonate injured sensory nerves. FEBSLett., 2000. 467(2-3): p. 249-52; Ruangsri, S., et al., Relationship ofaxonal voltage-gated sodium channel 1.8 (Na_(V)1.8) mRNA accumulation tosciatic nerve injury-induced painful neuropathy in rats. J Biol. Chem.286(46): p. 39836-47). The small DRG neurons where Na_(V)1.8 isexpressed include the nociceptors involved in pain signaling. Na_(V)1.8mediates large amplitude action potentials in small neurons of thedorsal root ganglia (Blair, N. T. and B. P. Bean, Roles of tetrodotoxin(TTX)-sensitive Na⁺ current, TTX-resistant Na⁺ current, and Ca²⁺ currentin the action potentials of nociceptive sensory neurons. J Neurosci.,2002. 22(23): p. 10277-90). Na_(V)1.8 is necessary for rapid repetitiveaction potentials in nociceptors, and for spontaneous activity ofdamaged neurons. (Choi, J. S. and S. G. Waxman, Physiologicalinteractions between Na_(V)1.7 and Na_(V)1.8 sodium channels: a computersimulation study. J Neurophysiol. 106(6): p. 3173-84; Renganathan, M.,T. R. Cummins, and S. G. Waxman, Contribution of Na(v)1.8 sodiumchannels to action potential electrogenesis in DRG neurons. J.Neurophysiol., 2001. 86(2): p. 629-40; Roza, C., et al., Thetetrodotoxin-resistant Na⁺ channel Na_(V)1.8 is essential for theexpression of spontaneous activity in damaged sensory axons of mice. J.Physiol., 2003. 550 (Pt 3): p. 921-6). In depolarized or damaged DRGneurons, Na_(V)1.8 appears to be a driver of hyper-excitablility (Rush,A. M., et al., A single sodium channel mutation produces hyper- orhypoexcitability in different types of neurons. Proc. Natl. Acad. Sci.USA, 2006. 103(21): p. 8245-50). In some animal pain models, Na_(V)1.8mRNA expression levels have been shown to increase in the DRG (Sun, W.,et al., Reduced conduction failure of the main axon of polymodalnociceptive C-fibers contributes to painful diabetic neuropathy in rats.Brain, 135 (Pt 2): p. 359-75; Strickland, I. T., et al., Changes in theexpression of Na_(V)1.7, Na_(V)1.8 and Na_(V)1.9 in a distinctpopulation of dorsal root ganglia innervating the rat knee joint in amodel of chronic inflammatory joint pain. Eur. J. Pain, 2008. 12(5): p.564-72; Qiu, F., et al., Increased expression of tetrodotoxin-resistantsodium channels Na_(V)1.8 and Na_(V)1.9 within dorsal root ganglia in arat model of bone cancer pain. Neurosci. Lett., 512(2): p. 61-6).

The primary drawback to some known Na_(V) inhibitors is their poortherapeutic window, and this is likely a consequence of their lack ofisoform selectivity. Since Na_(V)1.8 is primarily restricted to theneurons that sense pain, selective Na_(V)1.8 blockers are unlikely toinduce the adverse events common to non-selective Na_(V) blockers.Accordingly, there remains a need to develop additional Na_(V) channelmodulators, preferably those that are highly potent and selective forNa_(V)1.8.

SUMMARY

In one aspect, the invention relates to a compound described herein, ora pharmaceutically acceptable salt thereof.

In another aspect, the invention relates to a pharmaceutical compositioncomprising the compound, or a pharmaceutically acceptable salt thereof,and one or more pharmaceutically acceptable carriers or vehicles.

In still another aspect, the invention relates to a method of inhibitinga voltage gated sodium channel in a subject by administering thecompound, pharmaceutically acceptable salt, or pharmaceuticalcomposition to the subject.

In yet another aspect, the invention relates to a method of treating orlessening the severity in a subject of a variety of diseases, disorders,or conditions, including, but not limited to, chronic pain, gut pain,neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain,cancer pain, idiopathic pain, postsurgical pain (e.g., bunionectomypain, herniorrhaphy pain, or abdominoplasty pain), visceral pain,multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence,pathological cough, and cardiac arrhythmia, by administering thecompound, pharmaceutically acceptable salt, or pharmaceuticalcomposition to the subject.

DETAILED DESCRIPTION

In one aspect, the invention relates to a compound of formula (I) or(II)

or a pharmaceutically acceptable salt thereof, wherein R, R_(3a),R_(4a), R_(1b), R_(3b), R_(4b), R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, andR₁₃ are defined as described herein.

For purposes of this invention, the chemical elements are identified inaccordance with the Periodic Table of the Elements, CAS version,Handbook of Chemistry and Physics, 75^(th) Ed. Additionally, generalprinciples of organic chemistry are described in “Organic Chemistry,”Thomas Sorrell, University Science Books, Sausalito: 1999, and “March'sAdvanced Organic Chemistry,” 5^(th) Ed., Ed.: Smith, M. B. and March,J., John Wiley & Sons, New York: 2001, the entire contents of which arehereby incorporated by reference.

As used herein, the term “compounds of the invention” refers to thecompounds of formulas (I) and (II), and all of the embodiments thereof,as described herein, and to the compounds identified in Tables A, B, C,and D.

As described herein, the compounds of the invention comprise multiplevariable groups (e.g., R, R_(3a), R₅, etc.). As one of ordinary skill inthe art will recognize, combinations of groups envisioned by thisinvention are those combinations that result in the formation of stableor chemically feasible compounds. The term “stable,” in this context,refers to compounds that are not substantially altered when subjected toconditions to allow for their production, detection, and preferablytheir recovery, purification, and use for one or more of the purposesdisclosed herein. In some embodiments, a stable compound or chemicallyfeasible compound is one that is not substantially altered when kept ata temperature of 40° C. or less, in the absence of moisture or otherchemically reactive conditions, for at least a week.

As used herein, the term “substituted,” refers to a group in which oneor more hydrogen radicals has been replaced with a specifiedsubstituent. Unless otherwise indicated, a substituted group can have asubstituent at any substitutable position of the group, and when morethan one position in any given structure can be substituted with morethan one substituent selected from a specified group, the substituentcan be either the same or different at every position. As one ofordinary skill in the art will recognize, substituted groups envisionedby this invention are those that result in the formation of stable orchemically feasible compounds.

As used herein, the term “halo” means F, Cl, Br or I.

As used herein, the term “alkyl” refers to a straight or branchedhydrocarbon chain radical group consisting solely of carbon and hydrogenatoms, containing no unsaturation, and having the specified number ofcarbon atoms, which is attached to the rest of the molecule by a singlebond. For example, a “C₁-C₆ alkyl” group is an alkyl group havingbetween one and six carbon atoms.

As used herein, the term “haloalkyl” refers to an alkyl group having thespecified number of carbon atoms, wherein one or more of the hydrogenatoms of the alkyl group are replaced by halo groups. For example, a“C₁-C₆ haloalkyl” group is an alkyl group having between one and sixcarbon atoms, wherein one or more of the hydrogen atoms of the alkylgroup are replaced by halo groups.

As used herein, the term “alkoxy” refers to a radical of the formula—OR_(a) where R_(a) is an alkyl group having the specified number ofcarbon atoms. For example, a “C₁-C₆ alkoxy” group is a radical of theformula —OR_(a) where R_(a) is an alkyl group having the between one andsix carbon atoms.

As used herein, the term “haloalkoxy” refers to an alkoxy group havingthe specified number of carbon atoms, wherein one or more of thehydrogen atoms of the of the alkyl group are replaced by halo groups.

As used herein, the term “alkylsulfanyl” refers to a radical of theformula —SR_(a) where R_(a) is an alkyl group having the specifiednumber of carbon atoms. For example, a “C₁-C₆ alkylsulfanyl” group is aradical of the formula —SR_(a) where R_(a) is an alkyl group having thebetween one and six carbon atoms.

As used herein, the term “cycloalkyl” refers to a stable, non-aromatic,mono- or bicyclic (fused, bridged, or spiro) saturated hydrocarbonradical consisting solely of carbon and hydrogen atoms, having thespecified number of carbon ring atoms, and which is attached to the restof the molecule by a single bond.

As used herein, the term “cycloalkenyl” refers to a stable,non-aromatic, mono- or bicyclic (fused, bridged, or spiro) unsaturatedhydrocarbon radical consisting solely of carbon and hydrogen atoms,having the specified number of carbon ring atoms and one or morecarbon-carbon double bonds in the ring, and which is attached to therest of the molecule by a single bond.

As used herein, the term “heteroaryl” refers to a stable, aromatic,mono- or bicyclic ring radical having the specified number of ring atomsand comprising one or more heteroatoms individually selected fromnitrogen, oxygen and sulfur.

As used herein, the term “heterocyclyl” refers to a stable,non-aromatic, mono- or bicyclic (fused, bridged, or spiro) saturated orunsaturated radical, having the specified number of ring atoms,including one or more ring heteroatoms selected from nitrogen, oxygenand sulfur, and which is attached to the rest of the molecule by asingle bond.

As used herein, the term “heterocycloalkyl” refers to a stable,non-aromatic, mono- or bicyclic (fused, bridged, or spiro) saturatedradical, having the specified number of ring atoms, including one ormore ring heteroatoms selected from nitrogen, oxygen and sulfur, andwhich is attached to the rest of the molecule by a single bond.

As used herein, the term “heterocycloalkenyl” refers to a stable,non-aromatic, mono- or bicyclic (fused, bridged, or spiro) unsaturatedhydrocarbon radical, having the specified number of ring atoms,including one or more ring heteroatoms selected from nitrogen, oxygenand sulfur, and one or more carbon-carbon or carbon-heteroatom doublebonds in the ring, and which is attached to the rest of the molecule bya single bond.

As used herein, “*6” and “*7” in the following structure designate thecarbon atom in formula (I) or (II) to which R₆ and R₇, respectively, areattached.

Unless otherwise specified, the compounds of the invention, whetheridentified by chemical name or chemical structure, include allstereoisomers (e.g., enantiomers and diastereomers), double bond isomers(e.g., (Z) and (E)), conformational isomers, and tautomers, of thecompounds identified by the chemical names and chemical structuresprovided herein. In addition, single stereoisomers, double bond isomers,conformation isomers, and tautomers as well as mixtures ofstereoisomers, double bond isomers, conformation isomers, and tautomersare within the scope of the invention.

As used herein, in any chemical structure or formula, a bold or hashedstraight bond attached to a stereocenter of a compound, such as in

denotes the relative stereochemistry of the stereocenter, relative toother stereocenter(s) to which bold or hashed straight bonds areattached.

As used herein, the term “compound,” when referring to the compounds ofthe invention, refers to a collection of molecules having identicalchemical structures, except that there may be isotopic variation amongthe constituent atoms of the molecules. The term “compound” includessuch a collection of molecules without regard to the purity of a givensample containing the collection of molecules. Thus, the term “compound”includes such a collection of molecules in pure form, in a mixture(e.g., solution, suspension, or colloid) with one or more othersubstances, or in the form of a hydrate, solvate, or co-crystal.

In the specification and claims, unless otherwise specified, any atomnot specifically designated as a particular isotope in any compound ofthe invention is meant to represent any stable isotope of the specifiedelement. In the Examples, where an atom is not specifically designatedas a particular isotope in any compound of the invention, no effort wasmade to enrich that atom in a particular isotope, and therefore a personof ordinary skill in the art would understand that such atom likely waspresent at approximately the natural abundance isotopic composition ofthe specified element.

As used herein, the term “stable,” when referring to an isotope, meansthat the isotope is not known to undergo spontaneous radioactive decay.Stable isotopes include, but are not limited to, the isotopes for whichno decay mode is identified in V. S. Shirley & C. M. Lederer, IsotopesProject, Nuclear Science Division, Lawrence Berkeley Laboratory, Tableof Nuclides (January 1980).

As used herein in the specification and claims, “H” refers to hydrogenand includes any stable isotope of hydrogen, namely ¹H and D. In theExamples, where an atom is designated as “H,” no effort was made toenrich that atom in a particular isotope of hydrogen, and therefore aperson of ordinary skill in the art would understand that such hydrogenatom likely was present at approximately the natural abundance isotopiccomposition of hydrogen.

As used herein, “¹H” refers to protium. Where an atom in a compound ofthe invention, or a pharmaceutically acceptable salt thereof, isdesignated as protium, protium is present at the specified position atat least the natural abundance concentration of protium.

As used herein, “D,” “d,” and “²H” refer to deuterium.

In some embodiments, the compounds of the invention, andpharmaceutically acceptable salts thereof, include each constituent atomat approximately the natural abundance isotopic composition of thespecified element.

In some embodiments, the compounds of the invention, andpharmaceutically acceptable salts thereof, include one or more atomshaving an atomic mass or mass number which differs from the atomic massor mass number of the most abundant isotope of the specified element(“isotope-labeled” compounds and salts). Examples of stable isotopeswhich are commercially available and suitable for the invention includewithout limitation isotopes of hydrogen, carbon, nitrogen, oxygen, andphosphorus, for example ²H, ¹³C, ¹⁵N, ¹⁸O, ¹⁷O, and ³¹P, respectively.

The isotope-labeled compounds and salts can be used in a number ofbeneficial ways, including as medicaments. In some embodiments, theisotope-labeled compounds and salts are deuterium (2H)-labeled.Deuterium (²H)-labeled compounds and salts are therapeutically usefulwith potential therapeutic advantages over the non-²H-labeled compounds.In general, deuterium (²H)-labeled compounds and salts can have highermetabolic stability as compared to those that are not isotope-labeledowing to the kinetic isotope effect described below. Higher metabolicstability translates directly into an increased in vivo half-life orlower dosages, which under most circumstances would represent apreferred embodiment of the present invention. The isotope-labeledcompounds and salts can usually be prepared by carrying out theprocedures disclosed in the synthesis schemes, the examples and therelated description, replacing a non-isotope-labeled reactant by areadily available isotope-labeled reactant.

The deuterium (²H)-labeled compounds and salts can manipulate the rateof oxidative metabolism of the compound by way of the primary kineticisotope effect. The primary kinetic isotope effect is a change of therate for a chemical reaction that results from exchange of isotopicnuclei, which in turn is caused by the change in ground state energiesof the covalent bonds involved in the reaction. Exchange of a heavierisotope usually results in a lowering of the ground state energy for achemical bond and thus causes a reduction in the rate-limiting bondbreakage. If the bond breakage occurs in or in the vicinity of asaddle-point region along the coordinate of a multi-product reaction,the product distribution ratios can be altered substantially. Forexplanation: if deuterium is bonded to a carbon atom at anon-exchangeable position, rate differences of k_(H)/k_(D)=2-7 aretypical. For a further discussion, see S. L. Harbeson and R. D. Tung,Deuterium In Drug Discovery and Development, Ann. Rep. Med. Chem. 2011,46, 403-417, incorporated in its entirety herein by reference.

The concentration of an isotope (e.g., deuterium) incorporated at agiven position of an isotope-labeled compound of the invention, or apharmaceutically acceptable salt thereof, may be defined by the isotopicenrichment factor. The term “isotopic enrichment factor,” as usedherein, means the ratio between the abundance of an isotope at a givenposition in an isotope-labeled compound (or salt) and the naturalabundance of the isotope.

Where an atom in a compound of the invention, or a pharmaceuticallyacceptable salt thereof, is designated as deuterium, such compound (orsalt) has an isotopic enrichment factor for such atom of at least 3000(45% deuterium incorporation). In some embodiments, the isotopicenrichment factor is at least 3500 (52.5% deuterium incorporation), atleast 4000 (60% deuterium incorporation), at least 4500 (67.5% deuteriumincorporation), at least 5000 (75% deuterium incorporation), at least5500 (82.5% deuterium incorporation), at least 6000 (90% deuteriumincorporation), at least 6333.3 (95% deuterium incorporation), at least6466.7 (97% deuterium incorporation), at least 6600 (99% deuteriumincorporation), or at least 6633.3 (99.5% deuterium incorporation).

In one aspect, the invention relates to a compound of formula (I) or(II)

or a pharmaceutically acceptable salt thereof, wherein:

each R is independently H or C₁-C₆ alkyl;

R_(3a) is H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆haloalkoxy;

R_(4a) is H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆haloalkoxy;

R_(1b) is H, halo, C₁-C₆ alkyl, C1-C₆ haloalkyl, C1-C₆ alkoxy, or C₁-C₆haloalkoxy;

R_(3b) is H, halo, C₁-C₆ alkyl, C1-C₆ haloalkyl, C1-C₆ alkoxy, or C₁-C₆haloalkoxy;

R_(4b) is H, halo, C₁-C₆ alkyl, C1-C₆ haloalkyl, C1-C₆ alkoxy, or C₁-C₆haloalkoxy;

R₅, R₆, R₇, and R₈ are defined as follows:

(i) R₅, R₆, and R₇ are each independently H, halo, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; and R₈ is C₁-C₆ alkyl;

(ii) R₅ is W—(CH₂)_(n)—R_(z), C1-C₆ alkylsulfanyl, —O—(CH₂)_(p)—R_(w),or —O—(CH₂)_(p)—N(C₁-C₆ alkyl)₂; R₆ and R₇ are each independently H,halo, C₁-C₆ alkyl, C1-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy;and R8 is H;

(iii) R₅ and R₆ are each independently H, halo, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; R₇ is W—(CH₂)_(n)—R_(z),—C≡C—R_(x), or 3-6 membered cycloalkyl or phenyl, wherein said 3-6membered cycloalkyl or phenyl is substituted with 1-3 substituentsselected from a group consisting of C₁-C₆ alkoxy, CN, and —C(O)NH₂; andR₈ is H; or

(iv) R₅ is H, halo, C1-C₆ alkyl, C1-C₆ haloalkyl, C1-C₆ alkoxy, or C1-C₆haloalkoxy; R₆ and R₇,

together with the carbon atoms to which they are attached, form a ringof formula R₁₄; and R₈ is H;

R₉ is H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆haloalkoxy;

R₁₀ is H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆haloalkoxy;

R₁₁ is H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆haloalkoxy;

R₁₂ is H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆haloalkoxy;

R₁₃ is H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆haloalkoxy;

each R₁₄ is independently H, halo, C₁-C₄ alkyl, or C₁-C₄ haloalkyl;

each W is independently O or a single bond;

R_(x) is C₁-C₆ alkyl or 3-6 membered cycloalkyl, wherein said 3-6membered cycloalkyl may be unsubstituted or may be substituted with 1-3substituents selected from a group consisting of halo, C₁-C₆ alkyl, andC₁-C₆ haloalkyl;

each R_(w) is independently 3-6 membered cycloalkyl, phenyl, or 5-6membered heteroaryl, wherein said 3-6 membered cycloalkyl, phenyl, or5-6 membered heteroaryl may be unsubstituted or may be substituted with1-3 substituents selected from a group consisting of halo, C₁-C₆ alkyl,and C₁-C₆ haloalkyl;

R_(z) is 3-6 membered heterocyclyl, 7-8 membered cycloalkyl, or 4-8membered cycloalkenyl, wherein said 3-6 membered heterocyclyl, 7-8membered cycloalkyl, or 4-8 membered cycloalkenyl may be unsubstitutedor may be substituted with 1-3 substituents selected from a groupconsisting of halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, and C₁-C₆ alkoxy, orwherein 2 substituents together with the atom to which they are attachedform a 5-6 membered heterocyclyl ring;

n is 0 or 1; and

p is 2 or 3.

In some embodiments, the invention relates to a compound of formula (I)or (II), or a pharmaceutically acceptable salt thereof, wherein each Ris H. In other embodiments, each R is independently C₁-C₆ alkyl.

In some embodiments, the invention relates to a compound of formula (I)or (II), or a pharmaceutically acceptable salt thereof, wherein R_(3a)and R_(4a) are each H.

In some embodiments, the invention relates to a compound of formula (I)or (II), or a pharmaceutically acceptable salt thereof, wherein R_(1b),R_(3b), and R_(4b) are each H.

In some embodiments, the invention relates to a compound of formula (I)or (II), or a pharmaceutically acceptable salt thereof, wherein R₅, R₆,and R₇ are each independently H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl,C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; and R₈ is C₁-C₆ alkyl. In otherembodiments, R₅ is H; R₆ is C₁-C₆ haloalkyl; R₇ is H; and R₈ is C₁-C₆alkyl. In other embodiments, R₅ is H; R₆ is CF₃; R₇ is H; and R₈ is CH₃.

In some embodiments, the invention relates to a compound of formula (I)or (II), or a pharmaceutically acceptable salt thereof, wherein R₅ isW—(CH₂)_(n)—R_(z), C₁-C₆ alkylsulfanyl, —O—(CH₂)_(p)—R_(w), or—O—(CH₂)_(p)—N(C₁-C₆ alkyl)₂; R₆ and R₇ are each independently H, halo,C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; and R₈is H. In other embodiments, R₅ is W—(CH₂)_(n)—R_(z); R₆ and R₇ are eachindependently H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy; and R₈ is H. In other embodiments, R₅ is O—R_(z), andR_(z) is 3-6 membered heterocyclyl, wherein said 3-6 memberedheterocyclyl may be unsubstituted or may be substituted with 1-3substituents selected from a group consisting of halo, C₁-C₆ alkyl,C₁-C₆ haloalkyl, and C₁-C₆ alkoxy; R₆ is C₁-C₆ haloalkyl; R₇ is H; andR₈ is H. In other embodiments, R₅ is O—R_(z), and R_(z) is 3-6 memberedheterocyclyl; R₆ is C₁-C₆ haloalkyl; R₇ is H; and R₈ is H. In otherembodiments, R₅ is O—R_(z), and R_(z) is oxetanyl or tetrahydrofuranyl;R₆ is C₁-C₆ haloalkyl; R₇ is H; and R₈ is H. In other embodiments, R₅ isC₁-C₆ alkylsulfanyl; R₆ and R₇ are each independently H, halo, C₁-C₆alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; and R₈ is H.In other embodiments, R₅ is C₁-C₆ alkylsulfanyl; R₆ is C₁-C₆ haloalkyl;R₇ is H; and R₈ is H. In other embodiments, R₅ is —O—(CH₂)_(p)—R_(w); R₆and R₇ are each independently H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl,C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; and R₈ is H. In other embodiments, R₅is —O—(CH₂)_(p)—R_(w); R₆ is C₁-C₆ haloalkyl; R₇ is H; and R₈ is H. Inother embodiments, R₅ is —O—(CH₂)_(p)—R_(w), and R_(w) is 3-6 memberedcycloalkyl, wherein said 3-6 membered cycloalkyl may be unsubstituted ormay be substituted with 1-3 substituents selected from a groupconsisting of halo, C₁-C₆ alkyl, and C₁-C₆ haloalkyl; R₆ is C₁-C₆haloalkyl; R₇ is H; and R₈ is H. In other embodiments, R₅ is—O—(CH₂)_(p)—R_(w), and R_(w) is 3-6 membered cycloalkyl; R₆ is C₁-C₆haloalkyl; R₇ is H; and R₈ is H. In other embodiments, R₅ is—O—(CH₂)₂—R_(w), and R_(w) is 3-6 membered cycloalkyl; R₆ is C₁-C₆haloalkyl; R₇ is H; and R₈ is H. In other embodiments, R₅ is—O—(CH₂)_(p)—N(C₁-C₆ alkyl)₂; R₆ and R₇ are each independently H, halo,C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; and R₈is H. In other embodiments, R₅ is —O—(CH₂)_(p)—N(CH₃)₂; R₆ is C₁-C₆haloalkyl; R₇ is H; and R₈ is H. In other embodiments, R₅ is—O—(CH₂)₂—N(C₁-C₆ alkyl)₂; R₆ is C₁-C₆ haloalkyl; R₇ is H; and R₈ is H.In other embodiments, R₅ is

SCH₃,

or O(CH₂)₂N(CH₃)₂; R₆ is CF₃; R₇ is H; and R₈ is H. In otherembodiments, R₅ is

R₆ is CF₃; R₇ is H; and R₈ is H. In other embodiments, R₅ is SCH₃; R₆ isCF₃; R₇ is H; and R₈ is H. In other embodiments, R₅ is

R₆ is CF₃; R₇ is H; and R₈ is H. In other embodiments, R₅ isO(CH₂)₂N(CH₃)₂; R₆ is CF₃; R₇ is H; and R₈ is H.

In some embodiments, the invention relates to a compound of formula (I)or (II), or a pharmaceutically acceptable salt thereof, wherein R₅ andR₆ are each independently H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆alkoxy, or C₁-C₆ haloalkoxy; R₇ is W—(CH₂)_(n)—R_(z), —C≡C—R_(x), or 3-6membered cycloalkyl or phenyl, wherein said 3-6 membered cycloalkyl orphenyl is substituted with 1-3 substituents selected from a groupconsisting of C₁-C₆ alkoxy, CN, and —C(O)NH₂; and R₈ is H. In otherembodiments, R₅ and R₆ are each independently H, halo, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; R₇ isW—(CH₂)_(n)—R_(z); and R₈ is H. In other embodiments, R₅ and R₆ are eachindependently H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy; R₇ is W—R_(z); and R₈ is H. In other embodiments, R₅and R₆ are each independently H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl,C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; R₇ is R_(z); and R₈ is H. In otherembodiments, R₅ and R₆ are each independently H, halo, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; R₇ is R_(z), andR_(z) is 3-6 membered heterocyclyl, wherein said 3-6 memberedheterocyclyl may be unsubstituted or may be substituted with 1-3substituents selected from a group consisting of halo, C₁-C₆ alkyl,C₁-C₆ haloalkyl, and C₁-C₆ alkoxy, or wherein 2 substituents togetherwith the atom to which they are attached form a 5-6 memberedheterocyclyl ring; and R₈ is H. In other embodiments, R₅ and R₆ are eachindependently H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy; R₇ is R_(z), and R_(z) is 3-6 membered heterocyclyl,wherein said 3-6 membered heterocyclyl may be unsubstituted or may besubstituted with 1-3 substituents selected from a group consisting ofhalo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, and C₁-C₆ alkoxy; and R₈ is H. Inother embodiments, R₅ and R₆ are each independently H, halo, C₁-C₆alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; R₇ is R_(z),and R_(z) is 5-6 membered heterocyclyl, wherein said 5-6 memberedheterocyclyl may be unsubstituted or may be substituted with 1-3substituents selected from a group consisting of halo, C₁-C₆ alkyl,C₁-C₆ haloalkyl, and C₁-C₆ alkoxy; and R₈ is H. In other embodiments, R₅and R₆ are each independently H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl,C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; R₇ is R_(z), and R_(z) is 5-6membered heterocyclyl; and R₈ is H. In other embodiments, R₅ and R₆ areeach independently H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy,or C₁-C₆ haloalkoxy; R₇ is R_(z), and R_(z) is 5-6 memberedheterocycloalkyl, wherein said 5-6 membered heterocycloalkyl may beunsubstituted or may be substituted with 1-3 substituents selected froma group consisting of halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, and C₁-C₆alkoxy; and R₈ is H. In other embodiments, R₅ and R₆ are eachindependently H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy; R₇ is R_(z), and R_(z) is 5-6 memberedheterocycloalkyl; and R₈ is H. In other embodiments, R₅ and R₆ are eachindependently H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy; R₇ is R_(z), and R_(z) is tetrahydropyran-4-yl ortetrahydrofuran-3-yl, wherein said tetrahydropyran-4-yl ortetrahydrofuran-3-yl may be unsubstituted or may be substituted with 1-3substituents selected from a group consisting of halo, C₁-C₆ alkyl,C₁-C₆ haloalkyl, and C₁-C₆ alkoxy; and R₈ is H. In other embodiments, R₅and R₆ are each independently H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl,C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; R₇ is R_(z), and R_(z) istetrahydropyran-4-yl or tetrahydrofuran-3-yl; and R₈ is H. In otherembodiments, R₅ and R₆ are each independently H, halo, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; R₇ is R_(z), andR_(z) is 5-6 membered heterocycloalkenyl, wherein said 5-6 memberedheterocycloalkenyl may be unsubstituted or may be substituted with 1-3substituents selected from a group consisting of halo, C₁-C₆ alkyl,C₁-C₆ haloalkyl, and C₁-C₆ alkoxy; and R₈ is H. In other embodiments, R₅and R₆ are each independently H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl,C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; R₇ is R_(z), and R_(z) is 5-6membered heterocycloalkenyl; and R₈ is H. In other embodiments, R₅ andR₆ are each independently H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆alkoxy, or C₁-C₆ haloalkoxy; R₇ is R_(z), and R_(z) is3,4-dihydropyran-5-yl, 3,6-dihydropyran-4-yl, 2,5-dihydrofuran-3-yl, or2,3-dihydrofuran-4-yl, wherein said 3,4-dihydropyran-5-yl,3,6-dihydropyran-4-yl, 2,5-dihydrofuran-3-yl, or 2,3-dihydrofuran-4-ylmay be unsubstituted or may be substituted with 1-3 substituentsselected from a group consisting of halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl,and C₁-C₆ alkoxy; and R₈ is H. In other embodiments, R₅ and R₆ are eachindependently H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy; R₇ is R_(z), and R_(z) is 3,4-dihydropyran-5-yl,3,6-dihydropyran-4-yl, 2,5-dihydrofuran-3-yl, or 2,3-dihydrofuran-4-yl;and R₈ is H. In other embodiments, R₅ and R₆ are each independently H,halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy;R₇ is R_(z), and R_(z) is 7-8 membered cycloalkyl, wherein said 7-8membered cycloalkyl may be unsubstituted or may be substituted with 1-3substituents selected from a group consisting of halo, C₁-C₆ alkyl,C₁-C₆ haloalkyl, and C₁-C₆ alkoxy, or wherein 2 substituents togetherwith the atom to which they are attached form a 5-6 memberedheterocyclyl ring; and R₈ is H. In other embodiments, R₅ and R₆ are eachindependently H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy; R₇ is R_(z), and R_(z) is 7-8 membered cycloalkyl; andR₈ is H. In other embodiments, R₅ and R₆ are each independently H, halo,C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; R₇ isR_(z), and R_(z) is 4-8 membered cycloalkenyl, wherein said 4-8 memberedcycloalkenyl may be unsubstituted or may be substituted with 1-3substituents selected from a group consisting of halo, C₁-C₆ alkyl,C₁-C₆ haloalkyl, and C₁-C₆ alkoxy, or wherein 2 substituents togetherwith the atom to which they are attached form a 5-6 memberedheterocyclyl ring; and R₈ is H. In other embodiments, R₅ and R₆ are eachindependently H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy; R₇ is R_(z), and R_(z) is 5-6 membered cycloalkenyl,wherein said 5-6 membered cycloalkenyl may be unsubstituted or may besubstituted with 1-3 substituents selected from a group consisting ofhalo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, and C₁-C₆ alkoxy, or wherein 2substituents together with the atom to which they are attached form a5-6 membered heterocyclyl ring; and R₈ is H. In other embodiments, R₅and R₆ are each independently H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl,C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; R₇ is R_(z), and R_(z) is 5-6membered cycloalkenyl, wherein said 5-6 membered cycloalkenyl may beunsubstituted or may be substituted with 1-3 substituents selected froma group consisting of halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, and C₁-C₆alkoxy; and R₈ is H. In other embodiments, R₅ and R₆ are eachindependently H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy; R₇ is R_(z), and R_(z) is 5-6 membered cycloalkenyl;and R₈ is H. In other embodiments, R₅ and R₆ are each independently H,halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy;R₇ is R_(z), and R_(z) is cyclohexen-1-yl or cyclopenten-1-yl, whereinsaid cyclohexen-1-yl or cyclopenten-1-yl may be unsubstituted or may besubstituted with 1-3 substituents selected from a group consisting ofhalo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, and C₁-C₆ alkoxy, or wherein 2substituents together with the atom to which they are attached form a5-6 membered heterocyclyl ring; and R₈ is H. In other embodiments, R₅and R₆ are each independently H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl,C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; R₇ is R_(z), and R_(z) iscyclohexen-1-yl or cyclopenten-1-yl, wherein said cyclohexen-1-yl orcyclopenten-1-yl may be unsubstituted or may be substituted with 1-3substituents selected from a group consisting of halo, C₁-C₆ alkyl,C₁-C₆ haloalkyl, and C₁-C₆ alkoxy; and R₈ is H. In other embodiments, R₅and R₆ are each independently H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl,C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; R₇ is R_(z), and R_(z) iscyclohexen-1-yl or cyclopenten-1-yl; and R₈ is H. In other embodiments,R₅ and R₆ are each independently H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl,C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; R₇ is O—R_(z); and R₈ is H. In otherembodiments, R₅ and R₆ are each independently H, halo, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; R₇ is O—R_(z), andR_(z) is R_(z) is 4-8 membered cycloalkenyl, wherein said 4-8 memberedcycloalkenyl may be unsubstituted or may be substituted with 1-3substituents selected from a group consisting of halo, C₁-C₆ alkyl,C₁-C₆ haloalkyl, and C₁-C₆ alkoxy; and R₈ is H. In other embodiments, R₅and R₆ are each independently H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl,C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; R₇ is O—R_(z), and R_(z) is R_(z) iscyclobutenyl, wherein said cyclobutenyl may be unsubstituted or may besubstituted with 1-3 substituents selected from a group consisting ofhalo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, and C₁-C₆ alkoxy; and R₈ is H.

In other embodiments, R₅ is H, halo, or C₁-C₆ alkyl; R₆ is H; R₇ isW—(CH₂)_(n)—R_(z); and R₈ is H. In other embodiments, R₅ is H, halo, orC₁-C₆ alkyl; R₆ is H; R₇ is W—R_(z); and R₈ is H. In other embodiments,R₅ is H, halo, or C₁-C₆ alkyl; R₆ is H; R₇ is R_(z); and R₈ is H. Inother embodiments, R₅ is H, halo, or C₁-C₆ alkyl; R₆ is H; R₇ is R_(z),and R_(z) is 3-6 membered heterocyclyl, wherein said 3-6 memberedheterocyclyl may be unsubstituted or may be substituted with 1-3substituents selected from a group consisting of halo, C₁-C₆ alkyl,C₁-C₆ haloalkyl, and C₁-C₆ alkoxy, or wherein 2 substituents togetherwith the atom to which they are attached form a 5-6 memberedheterocyclyl ring; and R₈ is H. In other embodiments, R₅ is H, halo, orC₁-C₆ alkyl; R₆ is H; R₇ is R_(z), and R_(z) is 3-6 memberedheterocyclyl, wherein said 3-6 membered heterocyclyl may beunsubstituted or may be substituted with 1-3 substituents selected froma group consisting of halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, and C₁-C₆alkoxy; and R₈ is H. In other embodiments, R₅ is H, halo, or C₁-C₆alkyl; R₆ is H; R₇ is R_(z), and R_(z) is 5-6 membered heterocyclyl,wherein said 5-6 membered heterocyclyl may be unsubstituted or may besubstituted with 1-3 substituents selected from a group consisting ofhalo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, and C₁-C₆ alkoxy; and R₈ is H. Inother embodiments, R₅ is H, halo, or C₁-C₆ alkyl; R₆ is H; R₇ is R_(z),and R_(z) is 5-6 membered heterocyclyl; and R₈ is H. In otherembodiments, R₈ is H, halo, or C₁-C₆ alkyl; R₆ is H; R₇ is R_(z), andR_(z) is 5-6 membered heterocycloalkyl, wherein said 5-6 memberedheterocycloalkyl may be unsubstituted or may be substituted with 1-3substituents selected from a group consisting of halo, C₁-C₆ alkyl,C₁-C₆ haloalkyl, and C₁-C₆ alkoxy; and R₈ is H. In other embodiments, R₈is H, halo, or C₁-C₆ alkyl; R₆ is H; R₇ is R_(z), and R_(z) is 5-6membered heterocycloalkyl; and R₈ is H. In other embodiments, R₈ is H,halo, or C₁-C₆ alkyl; R₆ is H; R₇ is R_(z), and R_(z) istetrahydropyran-4-yl or tetrahydrofuran-3-yl, wherein saidtetrahydropyran-4-yl or tetrahydrofuran-3-yl may be unsubstituted or maybe substituted with 1-3 substituents selected from a group consisting ofhalo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, and C₁-C₆ alkoxy; and R₈ is H. Inother embodiments, R₈ is H, halo, or C₁-C₆ alkyl; R₆ is H; R₇ is R_(z),and R_(z) is tetrahydropyran-4-yl or tetrahydrofuran-3-yl; and R₈ is H.In other embodiments, R₈ is H, halo, or C₁-C₆ alkyl; R₆ is H; R₇ isR_(z), and R_(z) is 5-6 membered heterocycloalkenyl, wherein said 5-6membered heterocycloalkenyl may be unsubstituted or may be substitutedwith 1-3 substituents selected from a group consisting of halo, C₁-C₆alkyl, C₁-C₆ haloalkyl, and C₁-C₆ alkoxy; and R₈ is H. In otherembodiments, R₈ is H, halo, or C₁-C₆ alkyl; R₆ is H; R₇ is R_(z), andR_(z) is 5-6 membered heterocycloalkenyl; and R₈ is H. In otherembodiments, R₈ is H, halo, or C₁-C₆ alkyl; R₆ is H; R₇ is R_(z), andR_(z) is 3,4-dihydropyran-5-yl, 3,6-dihydropyran-4-yl,2,5-dihydrofuran-3-yl, or 2,3-dihydrofuran-4-yl, wherein said3,4-dihydropyran-5-yl, 3,6-dihydropyran-4-yl, 2,5-dihydrofuran-3-yl, or2,3-dihydrofuran-4-yl may be unsubstituted or may be substituted with1-3 substituents selected from a group consisting of halo, C₁-C₆ alkyl,C₁-C₆ haloalkyl, and C₁-C₆ alkoxy; and R₈ is H. In other embodiments, R₈is H, halo, or C₁-C₆ alkyl; R₆ is H; R₇ is R_(z), and R_(z) is3,4-dihydropyran-5-yl, 3,6-dihydropyran-4-yl, 2,5-dihydrofuran-3-yl, or2,3-dihydrofuran-4-yl; and R₈ is H. In other embodiments, R₈ is H, halo,or C₁-C₆ alkyl; R₆ is H; R₇ is R_(z), and R_(z) is 7-8 memberedcycloalkyl, wherein said 7-8 membered cycloalkyl may be unsubstituted ormay be substituted with 1-3 substituents selected from a groupconsisting of halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, and C₁-C₆ alkoxy, orwherein 2 substituents together with the atom to which they are attachedform a 5-6 membered heterocyclyl ring; and R₈ is H. In otherembodiments, R₈ is H, halo, or C₁-C₆ alkyl; R₆ is H; R₇ is R_(z), andR_(z) is 7-8 membered cycloalkyl; and R₈ is H. In other embodiments, R₈is H, halo, or C₁-C₆ alkyl; R₆ is H; R₇ is R_(z), and R_(z) is 4-8membered cycloalkenyl, wherein said 4-8 membered cycloalkenyl may beunsubstituted or may be substituted with 1-3 substituents selected froma group consisting of halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, and C₁-C₆alkoxy, or wherein 2 substituents together with the atom to which theyare attached form a 5-6 membered heterocyclyl ring; and R₈ is H. Inother embodiments, R₈ is H, halo, or C₁-C₆ alkyl; R₆ is H; R₇ is R_(z),and R_(z) is 5-6 membered cycloalkenyl, wherein said 5-6 memberedcycloalkenyl may be unsubstituted or may be substituted with 1-3substituents selected from a group consisting of halo, C₁-C₆ alkyl,C₁-C₆ haloalkyl, and C₁-C₆ alkoxy, or wherein 2 substituents togetherwith the atom to which they are attached form a 5-6 memberedheterocyclyl ring; and R₈ is H. In other embodiments, R₅ is H, halo, orC₁-C₆ alkyl; R₆ is H; R₇ is R_(z), and R_(z) is 5-6 memberedcycloalkenyl, wherein said 5-6 membered cycloalkenyl may beunsubstituted or may be substituted with 1-3 substituents selected froma group consisting of halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, and C₁-C₆alkoxy; and R₈ is H. In other embodiments, R₅ is H, halo, or C₁-C₆alkyl; R₆ is H; R₇ is R_(z), and R_(z) is 5-6 membered cycloalkenyl; andR₈ is H. In other embodiments, R₅ is H, halo, or C₁-C₆ alkyl; R₆ is H;R₇ is R_(z), and R_(z) is cyclohexen-1-yl or cyclopenten-1-yl, whereinsaid cyclohexen-1-yl or cyclopenten-1-yl may be unsubstituted or may besubstituted with 1-3 substituents selected from a group consisting ofhalo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, and C₁-C₆ alkoxy, or wherein 2substituents together with the atom to which they are attached form a5-6 membered heterocyclyl ring; and R₈ is H. In other embodiments, R₅ isH, halo, or C₁-C₆ alkyl; R₆ is H; R₇ is R_(z), and R_(z) iscyclohexen-1-yl or cyclopenten-1-yl, wherein said cyclohexen-1-yl orcyclopenten-1-yl may be unsubstituted or may be substituted with 1-3substituents selected from a group consisting of halo, C₁-C₆ alkyl,C₁-C₆ haloalkyl, and C₁-C₆ alkoxy; and R₈ is H. In other embodiments, R₅is H, halo, or C₁-C₆ alkyl; R₆ is H; R₇ is R_(z), and R_(z) iscyclohexen-1-yl or cyclopenten-1-yl; and R₈ is H. In other embodiments,R₈ is H, halo, or C₁-C₆ alkyl; R₆ is H; R₇ is O—R_(z); and R₈ is H. Inother embodiments, R₅ is H, halo, or C₁-C₆ alkyl; R₆ is H; R₇ isO—R_(z), and R_(z) is R_(z) is 4-8 membered cycloalkenyl, wherein said4-8 membered cycloalkenyl may be unsubstituted or may be substitutedwith 1-3 substituents selected from a group consisting of halo, C₁-C₆alkyl, C₁-C₆ haloalkyl, and C₁-C₆ alkoxy; and R₈ is H. In otherembodiments, R₅ is H, halo, or C₁-C₆ alkyl; R₆ is H; R₇ is O—R_(z), andR_(z) is R_(z) is cyclobutenyl, wherein said cyclobutenyl may beunsubstituted or may be substituted with 1-3 substituents selected froma group consisting of halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, and C₁-C₆alkoxy; and R₈ is H.

In other embodiments, R₅ and R₆ are each independently H, halo, C₁-C₆alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; R₇ is—C≡C—R_(x); and R₈ is H. In other embodiments, R₅ and R₆ are eachindependently H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy; R₇ is —C≡C—R_(x), and R_(x) is C₁-C₆ alkyl; and R₈ isH. In other embodiments, R₅ and R₆ are each independently H, halo, C₁-C₆alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; R₇ is—C≡C—R_(x), and R_(x) is 3-6 membered cycloalkyl, wherein said 3-6membered cycloalkyl may be unsubstituted or may be substituted with 1-3substituents selected from a group consisting of halo; and R₈ is H. Inother embodiments, R₅ and R₆ are each independently H, halo, C₁-C₆alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; R₇ is—C≡C—R_(x), and R_(x) is 3-6 membered cycloalkyl, wherein said 3-6membered cycloalkyl may be unsubstituted or may be substituted with 1-3substituents selected from a group consisting of halo; and R₈ is H. Inother embodiments, R₅ and R₆ are each independently H, halo, C₁-C₆alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; R₇ is—C≡C—R_(x), and R_(x) is 3-6 membered cycloalkyl; and R₈ is H. In otherembodiments, R₅ and R₆ are each independently H, halo, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; R₇ is —C≡C—R_(x),and R_(x) is cyclopropyl or cyclobutyl; and R₈ is H.

In other embodiments, R₅ is H, halo, or C₁-C₆ alkyl; R₆ is H; R₇ is—C≡C—R_(x); and R₈ is H. In other embodiments, R₅ is H, halo, or C₁-C₆alkyl; R₆ is H; R₇ is —C≡C—R_(x), and R_(x) is C₁-C₆ alkyl; and R₈ is H.In other embodiments, R₅ is H, halo, or C₁-C₆ alkyl; R₆ is H; R₇ is—C≡C—R_(x), and R_(x) is 3-6 membered cycloalkyl, wherein said 3-6membered cycloalkyl may be unsubstituted or may be substituted with 1-3substituents selected from a group consisting of halo; and R₈ is H. Inother embodiments, R₅ is H, halo, or C₁-C₆ alkyl; R₆ is H; R₇ is—C≡C—R_(x), and R_(x) is 3-6 membered cycloalkyl, wherein said 3-6membered cycloalkyl may be unsubstituted or may be substituted with 1-3substituents selected from a group consisting of halo; and R₈ is H. Inother embodiments, R₅ is H, halo, or C₁-C₆ alkyl; R₆ is H; R₇ is—C≡C—R_(x), and R_(x) is 3-6 membered cycloalkyl; and R₈ is H. In otherembodiments, R₅ is H, halo, or C₁-C₆ alkyl; R₆ is H; R₇ is —C≡C—R_(x),and R_(x) is cyclopropyl or cyclobutyl; and R₈ is H.

In other embodiments, R₅ and R₆ are each independently H, halo, C₁-C₆alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; R₇ is 3-6membered cycloalkyl or phenyl, wherein said 3-6 membered cycloalkyl orphenyl is substituted with 1-3 substituents selected from a groupconsisting of C₁-C₆ alkoxy, CN, and —C(O)NH₂; and R₈ is H. In otherembodiments, R₅ and R₆ are each independently H, halo, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; R₇ is 3-6 memberedcycloalkyl, wherein said 3-6 membered cycloalkyl is substituted with 1-3substituents selected from a group consisting of C₁-C₆ alkoxy, CN, and—C(O)NH₂; and R₈ is H. In other embodiments, R₅ and R₆ are eachindependently H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy; R₇ is cyclohexyl, wherein said cyclohexyl issubstituted with 1-3 substituents selected from a group consisting ofC₁-C₆ alkoxy, CN, and —C(O)NH₂; and R₈ is H. In other embodiments, R₅and R₆ are each independently H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl,C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; R₇ is phenyl, wherein said phenyl issubstituted with 1-3 substituents selected from a group consisting ofC₁-C₆ alkoxy, CN, and —C(O)NH₂; and R₈ is H.

In other embodiments, R₅ is H, halo, or C₁-C₆ alkyl; R₆ is H; R₇ is 3-6membered cycloalkyl or phenyl, wherein said 3-6 membered cycloalkyl orphenyl is substituted with 1-3 substituents selected from a groupconsisting of C₁-C₆ alkoxy, CN, and —C(O)NH₂; and R₈ is H. In otherembodiments, R₅ is H, halo, or C₁-C₆ alkyl; R₆ is H; R₇ is 3-6 memberedcycloalkyl, wherein said 3-6 membered cycloalkyl is substituted with 1-3substituents selected from a group consisting of C₁-C₆ alkoxy, CN, and—C(O)NH₂; and R₈ is H. In other embodiments, R₈ is H, halo, or C₁-C₆alkyl; R₆ is H; R₇ is cyclohexyl, wherein said cyclohexyl is substitutedwith 1-3 substituents selected from a group consisting of C₁-C₆ alkoxy,CN, and —C(O)NH₂; and R₈ is H. In other embodiments, R₈ is H, halo, orC₁-C₆ alkyl; R₆ is H; R₇ is phenyl, wherein said phenyl is substitutedwith 1-3 substituents selected from a group consisting of C₁-C₆ alkoxy,CN, and —C(O)NH₂; and R₈ is H. In other embodiments, R₅ is H, F, or CH₃;R₆ is H; R₇ is

and R₈ is H. In other embodiments, R₅ is H, F, or CH₃; R₆ is H; R₇ is

and R₈ is H. In other embodiments, R₅ is H, F, or CH₃; R₆ is H; R₇ is

and R₈ is H. In other embodiments, R₅ is H, F, or CH₃; R₆ is H; R₇ is

and R₈ is H. In other embodiments, R₅ is H, F, or CH₃; R₆ is H; R₇ is

and R₈ is H. In other embodiments, R₅ is H, F, or CH₃; R₆ is H; R₇ is

and R₈ is H. In other embodiments, R₅ is H, F, or CH₃; R₆ is H; R₇ is

or and R₈ is H. In other embodiments, R₅ is H, F, or CH₃; R₆ is H; R₇ is

and R₈ is H. In other embodiments, R₅ is H, F, or CH₃; R₆ is H; R₇ is

and R₈ is H. In other embodiments, R₅ is H, F, or CH₃; R₆ is H; R₇ is

and R₈ is H.

In some embodiments, the invention relates to a compound of formula (I)or (II), or a pharmaceutically acceptable salt thereof, wherein R₅ is H,halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy;R₆ and R₇, together with the carbon atoms to which they are attached,form a ring of formula

and R₈ is H. In other embodiments, R₅ is H or halo; R₆ and R₇, togetherwith the carbon atoms to which they are attached, form a ring of formula

and R₈ is H. In other embodiments, R₅ is H or halo; R₆ and R₇, togetherwith the carbon atoms to which they are attached, form a ring of formula

and R₈ is H. In other embodiments, R₅ is H or F; R₆ and R₇, togetherwith the carbon atoms to which they are attached, form a ring of formula

and R₈ is H.

In some embodiments, the invention relates to a compound of formula (I)or (II), or a pharmaceutically acceptable salt thereof, wherein R₉ ishalo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy.In other embodiments, R₉ is H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₉ is H, halo, C₁-C₆haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₉is H, halo, C₁-C₆ alkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. In otherembodiments, R₉ is H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or C₁-C₆haloalkoxy. In other embodiments, R₉ is H, halo, C₁-C₆ alkyl, C₁-C₆haloalkyl, or C₁-C₆ alkoxy. In other embodiments, R₉ is C₁-C₆ alkoxy. Inother embodiments, R₉ is OCH₃, OC(¹H)₃, or OCD₃. In other embodiments,R₉ is OCH₃. In other embodiments, R₉ is OC(¹H)₃. In other embodiments,R₉ is OCD₃.

In some embodiments, the invention relates to a compound of formula (I)or (II), or a pharmaceutically acceptable salt thereof, wherein R₁₀ isH. In other embodiments, R₁₀ is halo. In other embodiments, R₁₀ is F.

In some embodiments, the invention relates to a compound of formula (I)or (II), or a pharmaceutically acceptable salt thereof, wherein R₁₁ ishalo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy.In other embodiments, R₁₁ is H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₁₁ is H, halo, C₁-C₆haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₁₁is H, halo, C₁-C₆ alkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. In otherembodiments, R₁₁ is H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or C₁-C₆haloalkoxy. In other embodiments, R₁₁ is H, halo, C₁-C₆ alkyl, C₁-C₆haloalkyl, or C₁-C₆ alkoxy. In other embodiments, R₁₁ is C₁-C₆haloalkoxy. In other embodiments, R₁₁ is OCF₃.

In some embodiments, the invention relates to a compound of formula (I)or (II), or a pharmaceutically acceptable salt thereof, wherein R₁₂ isH.

In some embodiments, the invention relates to a compound of formula (I)or (II), or a pharmaceutically acceptable salt thereof, wherein R₁₃ isH.

In some embodiments, the invention relates to a compound of formula (I)or (II), i.e., the compound in non-salt form.

In one aspect, the invention relates to a compound of formula (I)

or a pharmaceutically acceptable salt thereof, wherein:

each R is independently H or C₁-C₆ alkyl;

R_(3a) is H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆haloalkoxy;

R_(4a) is H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆haloalkoxy;

R₅, R₆, R₇, and R₈ are defined as follows:

(i) R₅, R₆, and R₇ are each independently H, halo, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; and R₈ is C₁-C₆ alkyl;

(ii) R₅ is W—(CH₂)_(n)—R_(z), C₁-C₆ alkylsulfanyl, —O—(CH₂)_(p)—R_(w),or —O—(CH₂)_(p)—N(C₁-C₆ alkyl)₂; R₆ and R₇ are each independently H,halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy;and R₈ is H;

(iii) R₅ and R₆ are each independently H, halo, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; R₇ is W—(CH₂)_(n)—R_(z),—C≡C—R_(x), or 3-6 membered cycloalkyl or phenyl, wherein said 3-6membered cycloalkyl or phenyl is substituted with 1-3 substituentsselected from a group consisting of C₁-C₆ alkoxy, CN, and —C(O)NH₂; andR₈ is H; or

(iv) R₈ is H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆haloalkoxy; R₆ and R₇, together with the carbon atoms to which they areattached, form a ring of formula

and R₈ is H;

R₉, R₁₀, R₁₁, R₁₂, and R₁₃ are each independently H, halo, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy;

each R₁₄ is independently H, halo, C₁-C₄ alkyl, or C₁-C₄ haloalkyl;

each W is independently O or a single bond;

R_(x) is C₁-C₆ alkyl or 3-6 membered cycloalkyl, wherein said 3-6membered cycloalkyl may be unsubstituted or may be substituted with 1-3substituents selected from a group consisting of halo, C₁-C₆ alkyl, andC₁-C₆ haloalkyl;

each R_(w) is independently 3-6 membered cycloalkyl, phenyl, or 5-6membered heteroaryl, wherein said 3-6 membered cycloalkyl, phenyl, or5-6 membered heteroaryl may be unsubstituted or may be substituted with1-3 substituents selected from a group consisting of halo, C₁-C₆ alkyl,and C₁-C₆ haloalkyl; R_(z) is 3-6 membered heterocyclyl, 7-8 memberedcycloalkyl, or 4-8 membered cycloalkenyl, wherein said 3-6 memberedheterocyclyl, 7-8 membered cycloalkyl, or 4-8 membered cycloalkenyl maybe unsubstituted or may be substituted with 1-3 substituents selectedfrom a group consisting of halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, and C₁-C₆alkoxy, or wherein 2 substituents together with the atom to which theyare attached form a 5-6 membered heterocyclyl ring;

n is 0 or 1; and

p is 2 or 3.

In some embodiments, the invention relates to a compound of formula (I),or a pharmaceutically acceptable salt thereof, wherein each R is H. Inother embodiments, each R is independently C₁-C₆ alkyl.

In some embodiments, the invention relates to a compound of formula (I),or a pharmaceutically acceptable salt thereof, wherein R_(3a) and R_(4a)are each H.

In some embodiments, the invention relates to a compound of formula (I),or a pharmaceutically acceptable salt thereof, wherein R_(1b), R_(3b),and R_(4b) are each H.

In some embodiments, the invention relates to a compound of formula (I),or a pharmaceutically acceptable salt thereof, wherein R₅, R₆, and R₇are each independently H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆alkoxy, or C₁-C₆ haloalkoxy; and R₈ is C₁-C₆ alkyl. In otherembodiments, R₅ is H; R₆ is C₁-C₆ haloalkyl; R₇ is H; and R₈ is C₁-C₆alkyl. In other embodiments, R₅ is H; R₆ is CF₃; R₇ is H; and R₈ is CH₃.

In some embodiments, the invention relates to a compound of formula (I),or a pharmaceutically acceptable salt thereof, wherein R₅ isW—(CH₂)_(n)—R_(z), C₁-C₆ alkylsulfanyl, —O—(CH₂)_(p)—R_(w), or—O—(CH₂)_(p)—N(C₁-C₆ alkyl)₂; R₆ and R₇ are each independently H, halo,C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; and R₈is H. In other embodiments, R₅ is W—(CH₂)_(n)—R_(z); R₆ and R₇ are eachindependently H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy; and R₈ is H. In other embodiments, R₅ is O—R_(z), andR_(z) is 3-6 membered heterocyclyl, wherein said 3-6 memberedheterocyclyl may be unsubstituted or may be substituted with 1-3substituents selected from a group consisting of halo, C₁-C₆ alkyl,C₁-C₆ haloalkyl, and C₁-C₆ alkoxy; R₆ is C₁-C₆ haloalkyl; R₇ is H; andR₈ is H. In other embodiments, R₅ is O—R_(z), and R_(z) is 3-6 memberedheterocyclyl; R₆ is C₁-C₆ haloalkyl; R₇ is H; and R₈ is H. In otherembodiments, R₅ is O—R_(z), and R_(z) is oxetanyl or tetrahydrofuranyl;R₆ is C₁-C₆ haloalkyl; R₇ is H; and R₈ is H. In other embodiments, R₅ isC₁-C₆ alkylsulfanyl; R₆ and R₇ are each independently H, halo, C₁-C₆alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; and R₈ is H.In other embodiments, R₅ is C₁-C₆ alkylsulfanyl; R₆ is C₁-C₆ haloalkyl;R₇ is H; and R₈ is H. In other embodiments, R₅ is —O—(CH₂)_(p)—R_(w); R₆and R₇ are each independently H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl,C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; and R₈ is H. In other embodiments, R₅is —O—(CH₂)_(p)—R_(w); R₆ is C₁-C₆ haloalkyl; R₇ is H; and R₈ is H. Inother embodiments, R₅ is —O—(CH₂)_(p)—R_(w), and R_(w) is 3-6 memberedcycloalkyl, wherein said 3-6 membered cycloalkyl may be unsubstituted ormay be substituted with 1-3 substituents selected from a groupconsisting of halo, C₁-C₆ alkyl, and C₁-C₆ haloalkyl; R₆ is C₁-C₆haloalkyl; R₇ is H; and R₈ is H. In other embodiments, R₅ is—O—(CH₂)_(p)—R_(w), and R_(w) is 3-6 membered cycloalkyl; R₆ is C₁-C₆haloalkyl; R₇ is H; and R₈ is H. In other embodiments, R₅ is—O—(CH₂)₂—R_(w), and R_(w) is 3-6 membered cycloalkyl; R₆ is C₁-C₆haloalkyl; R₇ is H; and R₈ is H. In other embodiments, R₅ is−0-(CH₂)_(p)—N(C₁-C₆ alkyl)₂; R₆ and R₇ are each independently H, halo,C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; and R₈is H. In other embodiments, R₅ is —O—(CH₂)_(p)—N(CH₃)₂; R₆ is C₁-C₆haloalkyl; R₇ is H; and R₈ is H. In other embodiments, R₅ is—O—(CH₂)₂—N(C₁-C₆ alkyl)₂; R₆ is C₁-C₆ haloalkyl; R₇ is H; and R₈ is H.In other embodiments, R₅ is

SCH₃,

or O(CH₂)₂N(CH₃)₂; R₆ is CF₃; R₇ is H; and R₅ is H. In otherembodiments, R₅ is

R₆ is CF₃; R₇ is H; and R₈ is H. In other embodiments, R₅ is SCH₃; R₆ isCF₃; R₇ is H; and R₈ is H. In other embodiments, R₅ is

R₆ is CF₃; R₇ is H; and R₈ is H. In other embodiments, R₅ isO(CH₂)₂N(CH₃)₂; R₆ is CF₃; R₇ is H; and R₈ is H.

In some embodiments, the invention relates to a compound of formula (I),or a pharmaceutically acceptable salt thereof, wherein R₅ and R₆ areeach independently H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy,or C₁-C₆ haloalkoxy; R₇ is W—(CH₂)_(n)—R_(z), —C≡C—R_(x), or 3-6membered cycloalkyl or phenyl, wherein said 3-6 membered cycloalkyl orphenyl is substituted with 1-3 substituents selected from a groupconsisting of C₁-C₆ alkoxy, CN, and —C(O)NH₂; and R₈ is H. In otherembodiments, R₅ and R₆ are each independently H, halo, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; R₇ isW—(CH₂)_(n)—R_(z); and R₈ is H. In other embodiments, R₅ and R₆ are eachindependently H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy; R₇ is W—R_(z); and R₈ is H. In other embodiments, R₅and R₆ are each independently H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl,C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; R₇ is R_(z); and R₈ is H. In otherembodiments, R₅ and R₆ are each independently H, halo, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; R₇ is R_(z), andR_(z) is 3-6 membered heterocyclyl, wherein said 3-6 memberedheterocyclyl may be unsubstituted or may be substituted with 1-3substituents selected from a group consisting of halo, C₁-C₆ alkyl,C₁-C₆ haloalkyl, and C₁-C₆ alkoxy, or wherein 2 substituents togetherwith the atom to which they are attached form a 5-6 memberedheterocyclyl ring; and R₈ is H. In other embodiments, R₅ and R₆ are eachindependently H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy; R₇ is R_(z), and R_(z) is 3-6 membered heterocyclyl,wherein said 3-6 membered heterocyclyl may be unsubstituted or may besubstituted with 1-3 substituents selected from a group consisting ofhalo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, and C₁-C₆ alkoxy; and R₈ is H. Inother embodiments, R₅ and R₆ are each independently H, halo, C₁-C₆alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; R₇ is R_(z),and R_(z) is 5-6 membered heterocyclyl, wherein said 5-6 memberedheterocyclyl may be unsubstituted or may be substituted with 1-3substituents selected from a group consisting of halo, C₁-C₆ alkyl,C₁-C₆ haloalkyl, and C₁-C₆ alkoxy; and R₈ is H. In other embodiments, R₅and R₆ are each independently H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl,C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; R₇ is R_(z), and R_(z) is 5-6membered heterocyclyl; and R₈ is H. In other embodiments, R₅ and R₆ areeach independently H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy,or C₁-C₆ haloalkoxy; R₇ is R_(z), and R_(z) is 5-6 memberedheterocycloalkyl, wherein said 5-6 membered heterocycloalkyl may beunsubstituted or may be substituted with 1-3 substituents selected froma group consisting of halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, and C₁-C₆alkoxy; and R₈ is H. In other embodiments, R₅ and R₆ are eachindependently H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy; R₇ is R_(z), and R_(z) is 5-6 memberedheterocycloalkyl; and R₈ is H. In other embodiments, R₅ and R₆ are eachindependently H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy; R₇ is R_(z), and R_(z) is tetrahydropyran-4-yl ortetrahydrofuran-3-yl, wherein said tetrahydropyran-4-yl ortetrahydrofuran-3-yl may be unsubstituted or may be substituted with 1-3substituents selected from a group consisting of halo, C₁-C₆ alkyl,C₁-C₆ haloalkyl, and C₁-C₆ alkoxy; and R₈ is H. In other embodiments, R₅and R₆ are each independently H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl,C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; R₇ is R_(z), and R_(z) istetrahydropyran-4-yl or tetrahydrofuran-3-yl; and R₈ is H. In otherembodiments, R₅ and R₆ are each independently H, halo, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; R₇ is R_(z), andR_(z) is 5-6 membered heterocycloalkenyl, wherein said 5-6 memberedheterocycloalkenyl may be unsubstituted or may be substituted with 1-3substituents selected from a group consisting of halo, C₁-C₆ alkyl,C₁-C₆ haloalkyl, and C₁-C₆ alkoxy; and R₈ is H. In other embodiments, R₅and R₆ are each independently H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl,C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; R₇ is R_(z), and R_(z) is 5-6membered heterocycloalkenyl; and R₈ is H. In other embodiments, R₅ andR₆ are each independently H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆alkoxy, or C₁-C₆ haloalkoxy; R₇ is R_(z), and R_(z) is3,4-dihydropyran-5-yl, 3,6-dihydropyran-4-yl, 2,5-dihydrofuran-3-yl, or2,3-dihydrofuran-4-yl, wherein said 3,4-dihydropyran-5-yl,3,6-dihydropyran-4-yl, 2,5-dihydrofuran-3-yl, or 2,3-dihydrofuran-4-ylmay be unsubstituted or may be substituted with 1-3 substituentsselected from a group consisting of halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl,and C₁-C₆ alkoxy; and R₈ is H. In other embodiments, R₅ and R₆ are eachindependently H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy; R₇ is R_(z), and R_(z) is 3,4-dihydropyran-5-yl,3,6-dihydropyran-4-yl, 2,5-dihydrofuran-3-yl, or 2,3-dihydrofuran-4-yl;and R₈ is H. In other embodiments, R₅ and R₆ are each independently H,halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy;R₇ is R_(z), and R_(z) is 7-8 membered cycloalkyl, wherein said 7-8membered cycloalkyl may be unsubstituted or may be substituted with 1-3substituents selected from a group consisting of halo, C₁-C₆ alkyl,C₁-C₆ haloalkyl, and C₁-C₆ alkoxy, or wherein 2 substituents togetherwith the atom to which they are attached form a 5-6 memberedheterocyclyl ring; and R₈ is H. In other embodiments, R₅ and R₆ are eachindependently H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy; R₇ is R_(z), and R_(z) is 7-8 membered cycloalkyl; andR₈ is H. In other embodiments, R₅ and R₆ are each independently H, halo,C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; R₇ isR_(z), and R_(z) is 4-8 membered cycloalkenyl, wherein said 4-8 memberedcycloalkenyl may be unsubstituted or may be substituted with 1-3substituents selected from a group consisting of halo, C₁-C₆ alkyl,C₁-C₆ haloalkyl, and C₁-C₆ alkoxy, or wherein 2 substituents togetherwith the atom to which they are attached form a 5-6 memberedheterocyclyl ring; and R₈ is H. In other embodiments, R₅ and R₆ are eachindependently H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy; R₇ is R_(z), and R_(z) is 5-6 membered cycloalkenyl,wherein said 5-6 membered cycloalkenyl may be unsubstituted or may besubstituted with 1-3 substituents selected from a group consisting ofhalo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, and C₁-C₆ alkoxy, or wherein 2substituents together with the atom to which they are attached form a5-6 membered heterocyclyl ring; and R₈ is H. In other embodiments, R₅and R₆ are each independently H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl,C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; R₇ is R_(z), and R_(z) is 5-6membered cycloalkenyl, wherein said 5-6 membered cycloalkenyl may beunsubstituted or may be substituted with 1-3 substituents selected froma group consisting of halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, and C₁-C₆alkoxy; and R₈ is H. In other embodiments, R₅ and R₆ are eachindependently H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy; R₇ is R_(z), and R_(z) is 5-6 membered cycloalkenyl;and R₈ is H. In other embodiments, R₅ and R₆ are each independently H,halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy;R₇ is R_(z), and R_(z) is cyclohexen-1-yl or cyclopenten-1-yl, whereinsaid cyclohexen-1-yl or cyclopenten-1-yl may be unsubstituted or may besubstituted with 1-3 substituents selected from a group consisting ofhalo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, and C₁-C₆ alkoxy, or wherein 2substituents together with the atom to which they are attached form a5-6 membered heterocyclyl ring; and R₈ is H. In other embodiments, R₅and R₆ are each independently H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl,C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; R₇ is R_(z), and R_(z) iscyclohexen-1-yl or cyclopenten-1-yl, wherein said cyclohexen-1-yl orcyclopenten-1-yl may be unsubstituted or may be substituted with 1-3substituents selected from a group consisting of halo, C₁-C₆ alkyl,C₁-C₆ haloalkyl, and C₁-C₆ alkoxy; and R₈ is H. In other embodiments, R₅and R₆ are each independently H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl,C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; R₇ is R_(z), and R_(z) iscyclohexen-1-yl or cyclopenten-1-yl; and R₈ is H. In other embodiments,R₅ and R₆ are each independently H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl,C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; R₇ is O—R_(z); and R₈ is H. In otherembodiments, R₅ and R₆ are each independently H, halo, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; R₇ is O—R_(z), andR_(z) is R_(z) is 4-8 membered cycloalkenyl, wherein said 4-8 memberedcycloalkenyl may be unsubstituted or may be substituted with 1-3substituents selected from a group consisting of halo, C₁-C₆ alkyl,C₁-C₆ haloalkyl, and C₁-C₆ alkoxy; and R₈ is H. In other embodiments, R₅and R₆ are each independently H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl,C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; R₇ is O—R_(z), and R_(z) is R_(z) iscyclobutenyl, wherein said cyclobutenyl may be unsubstituted or may besubstituted with 1-3 substituents selected from a group consisting ofhalo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, and C₁-C₆ alkoxy; and R₈ is H.

In other embodiments, R₅ is H, halo, or C₁-C₆ alkyl; R₆ is H; R₇ isW—(CH₂)_(n)—R_(z); and R₈ is H. In other embodiments, R₅ is H, halo, orC₁-C₆ alkyl; R₆ is H; R₇ is W—R_(z); and R₈ is H. In other embodiments,R₅ is H, halo, or C₁-C₆ alkyl; R₆ is H; R₇ is R_(z); and R₈ is H. Inother embodiments, R₅ is H, halo, or C₁-C₆ alkyl; R₆ is H; R₇ is R_(z),and R_(z) is 3-6 membered heterocyclyl, wherein said 3-6 memberedheterocyclyl may be unsubstituted or may be substituted with 1-3substituents selected from a group consisting of halo, C₁-C₆ alkyl,C₁-C₆ haloalkyl, and C₁-C₆ alkoxy, or wherein 2 substituents togetherwith the atom to which they are attached form a 5-6 memberedheterocyclyl ring; and R₈ is H. In other embodiments, R₅ is H, halo, orC₁-C₆ alkyl; R₆ is H; R₇ is R_(z), and R_(z) is 3-6 memberedheterocyclyl, wherein said 3-6 membered heterocyclyl may beunsubstituted or may be substituted with 1-3 substituents selected froma group consisting of halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, and C₁-C₆alkoxy; and R₈ is H. In other embodiments, R₈ is H, halo, or C₁-C₆alkyl; R₆ is H; R₇ is R_(z), and R_(z) is 5-6 membered heterocyclyl,wherein said 5-6 membered heterocyclyl may be unsubstituted or may besubstituted with 1-3 substituents selected from a group consisting ofhalo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, and C₁-C₆ alkoxy; and R₈ is H. Inother embodiments, R₅ is H, halo, or C₁-C₆ alkyl; R₆ is H; R₇ is R_(z),and R_(z) is 5-6 membered heterocyclyl; and R₈ is H. In otherembodiments, R₅ is H, halo, or C₁-C₆ alkyl; R₆ is H; R₇ is R_(z), andR_(z) is 5-6 membered heterocycloalkyl, wherein said 5-6 memberedheterocycloalkyl may be unsubstituted or may be substituted with 1-3substituents selected from a group consisting of halo, C₁-C₆ alkyl,C₁-C₆ haloalkyl, and C₁-C₆ alkoxy; and R₈ is H. In other embodiments, R₅is H, halo, or C₁-C₆ alkyl; R₆ is H; R₇ is R_(z), and R_(z) is 5-6membered heterocycloalkyl; and R₈ is H. In other embodiments, R₅ is H,halo, or C₁-C₆ alkyl; R₆ is H; R₇ is R_(z), and R_(z) istetrahydropyran-4-yl or tetrahydrofuran-3-yl, wherein saidtetrahydropyran-4-yl or tetrahydrofuran-3-yl may be unsubstituted or maybe substituted with 1-3 substituents selected from a group consisting ofhalo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, and C₁-C₆ alkoxy; and R₈ is H. Inother embodiments, R₅ is H, halo, or C₁-C₆ alkyl; R₆ is H; R₇ is R_(z),and R_(z) is tetrahydropyran-4-yl or tetrahydrofuran-3-yl; and R₈ is H.In other embodiments, R₅ is H, halo, or C₁-C₆ alkyl; R₆ is H; R₇ isR_(z), and R_(z) is 5-6 membered heterocycloalkenyl, wherein said 5-6membered heterocycloalkenyl may be unsubstituted or may be substitutedwith 1-3 substituents selected from a group consisting of halo, C₁-C₆alkyl, C₁-C₆ haloalkyl, and C₁-C₆ alkoxy; and R₈ is H. In otherembodiments, R₅ is H, halo, or C₁-C₆ alkyl; R₆ is H; R₇ is R_(z), andR_(z) is 5-6 membered heterocycloalkenyl; and R₈ is H. In otherembodiments, R₅ is H, halo, or C₁-C₆ alkyl; R₆ is H; R₇ is R_(z), andR_(z) is 3,4-dihydropyran-5-yl, 3,6-dihydropyran-4-yl,2,5-dihydrofuran-3-yl, or 2,3-dihydrofuran-4-yl, wherein said3,4-dihydropyran-5-yl, 3,6-dihydropyran-4-yl, 2,5-dihydrofuran-3-yl, or2,3-dihydrofuran-4-yl may be unsubstituted or may be substituted with1-3 substituents selected from a group consisting of halo, C₁-C₆ alkyl,C₁-C₆ haloalkyl, and C₁-C₆ alkoxy; and R₈ is H. In other embodiments, R₅is H, halo, or C₁-C₆ alkyl; R₆ is H; R₇ is R_(z), and R_(z) is3,4-dihydropyran-5-yl, 3,6-dihydropyran-4-yl, 2,5-dihydrofuran-3-yl, or2,3-dihydrofuran-4-yl; and R₈ is H. In other embodiments, R₅ is H, halo,or C₁-C₆ alkyl; R₆ is H; R₇ is R_(z), and R_(z) is 7-8 memberedcycloalkyl, wherein said 7-8 membered cycloalkyl may be unsubstituted ormay be substituted with 1-3 substituents selected from a groupconsisting of halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, and C₁-C₆ alkoxy, orwherein 2 substituents together with the atom to which they are attachedform a 5-6 membered heterocyclyl ring; and R₈ is H. In otherembodiments, R₅ is H, halo, or C₁-C₆ alkyl; R₆ is H; R₇ is R_(z), andR_(z) is 7-8 membered cycloalkyl; and R₈ is H. In other embodiments, R₅is H, halo, or C₁-C₆ alkyl; R₆ is H; R₇ is R_(z), and R_(z) is 4-8membered cycloalkenyl, wherein said 4-8 membered cycloalkenyl may beunsubstituted or may be substituted with 1-3 substituents selected froma group consisting of halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, and C₁-C₆alkoxy, or wherein 2 substituents together with the atom to which theyare attached form a 5-6 membered heterocyclyl ring; and R₈ is H. Inother embodiments, R₅ is H, halo, or C₁-C₆ alkyl; R₆ is H; R₇ is R_(z),and R_(z) is 5-6 membered cycloalkenyl, wherein said 5-6 memberedcycloalkenyl may be unsubstituted or may be substituted with 1-3substituents selected from a group consisting of halo, C₁-C₆ alkyl,C₁-C₆ haloalkyl, and C₁-C₆ alkoxy, or wherein 2 substituents togetherwith the atom to which they are attached form a 5-6 memberedheterocyclyl ring; and R₈ is H. In other embodiments, R₅ is H, halo, orC₁-C₆ alkyl; R₆ is H; R₇ is R_(z), and R_(z) is 5-6 memberedcycloalkenyl, wherein said 5-6 membered cycloalkenyl may beunsubstituted or may be substituted with 1-3 substituents selected froma group consisting of halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, and C₁-C₆alkoxy; and R₈ is H. In other embodiments, R₅ is H, halo, or C₁-C₆alkyl; R₆ is H; R₇ is R_(z), and R_(z) is 5-6 membered cycloalkenyl; andR₈ is H. In other embodiments, R₅ is H, halo, or C₁-C₆ alkyl; R₆ is H;R₇ is R_(z), and R_(z) is cyclohexen-1-yl or cyclopenten-1-yl, whereinsaid cyclohexen-1-yl or cyclopenten-1-yl may be unsubstituted or may besubstituted with 1-3 substituents selected from a group consisting ofhalo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, and C₁-C₆ alkoxy, or wherein 2substituents together with the atom to which they are attached form a5-6 membered heterocyclyl ring; and R₈ is H. In other embodiments, R₅ isH, halo, or C₁-C₆ alkyl; R₆ is H; R₇ is R_(z), and R_(z) iscyclohexen-1-yl or cyclopenten-1-yl, wherein said cyclohexen-1-yl orcyclopenten-1-yl may be unsubstituted or may be substituted with 1-3substituents selected from a group consisting of halo, C₁-C₆ alkyl,C₁-C₆ haloalkyl, and C₁-C₆ alkoxy; and R_(s) is H. In other embodiments,R₅ is H, halo, or C₁-C₆ alkyl; R₆ is H; R₇ is R_(z), and R_(z) iscyclohexen-1-yl or cyclopenten-1-yl; and R₈ is H. In other embodiments,R₅ is H, halo, or C₁-C₆ alkyl; R₆ is H; R₇ is O—R_(z); and R₈ is H. Inother embodiments, R₅ is H, halo, or C₁-C₆ alkyl; R₆ is H; R₇ isO—R_(z), and R_(z) is R_(z) is 4-8 membered cycloalkenyl, wherein said4-8 membered cycloalkenyl may be unsubstituted or may be substitutedwith 1-3 substituents selected from a group consisting of halo, C₁-C₆alkyl, C₁-C₆ haloalkyl, and C₁-C₆ alkoxy; and R₈ is H. In otherembodiments, R₅ is H, halo, or C₁-C₆ alkyl; R₆ is H; R₇ is O—R_(z), andR_(z) is R_(z) is cyclobutenyl, wherein said cyclobutenyl may beunsubstituted or may be substituted with 1-3 substituents selected froma group consisting of halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, and C₁-C₆alkoxy; and R₈ is H.

In other embodiments, R₅ and R₆ are each independently H, halo, C₁-C₆alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; R₇ is—C≡C—R_(x); and R₈ is H. In other embodiments, R₅ and R₆ are eachindependently H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy; R₇ is —C≡C—R_(x), and R, is C₁-C₆ alkyl; and R₈ is H.In other embodiments, R₅ and R₆ are each independently H, halo, C₁-C₆alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; R₇ is—C≡C—R_(x), and R, is 3-6 membered cycloalkyl, wherein said 3-6 memberedcycloalkyl may be unsubstituted or may be substituted with 1-3substituents selected from a group consisting of halo; and R₈ is H. Inother embodiments, R₅ and R₆ are each independently H, halo, C₁-C₆alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; R₇ is—C≡C—R_(x), and R_(x) is 3-6 membered cycloalkyl, wherein said 3-6membered cycloalkyl may be unsubstituted or may be substituted with 1-3substituents selected from a group consisting of halo; and R₈ is H. Inother embodiments, R₅ and R₆ are each independently H, halo, C₁-C₆alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; R₇ is—C≡C—R_(x), and R_(x) is 3-6 membered cycloalkyl; and R₈ is H. In otherembodiments, R₅ and R₆ are each independently H, halo, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; R₇ is —C≡C—R_(x),and R_(x) is cyclopropyl or cyclobutyl; and R₈ is H.

In other embodiments, R₅ is H, halo, or C₁-C₆ alkyl; R₆ is H; R₇ is—C≡C—R_(x); and R₈ is H. In other embodiments, R₅ is H, halo, or C₁-C₆alkyl; R₆ is H; R₇ is —C≡C—R_(x), and R_(x) is C₁-C₆ alkyl; and R₈ is H.In other embodiments, R₅ is H, halo, or C₁-C₆ alkyl; R₆ is H; R₇ is—C≡C—R_(x), and R_(x) is 3-6 membered cycloalkyl, wherein said 3-6membered cycloalkyl may be unsubstituted or may be substituted with 1-3substituents selected from a group consisting of halo; and R_(s) is H.In other embodiments, R₅ is H, halo, or C₁-C₆ alkyl; R₆ is H; R₇ is—C≡C—R_(x), and R_(x) is 3-6 membered cycloalkyl, wherein said 3-6membered cycloalkyl may be unsubstituted or may be substituted with 1-3substituents selected from a group consisting of halo; and R₈ is H. Inother embodiments, R₅ is H, halo, or C₁-C₆ alkyl; R₆ is H; R₇ is—C≡C—R_(x), and R_(x) is 3-6 membered cycloalkyl; and R₈ is H. In otherembodiments, R₅ is H, halo, or C₁-C₆ alkyl; R₆ is H; R₇ is —C≡C—R_(x),and R_(x) is cyclopropyl or cyclobutyl; and R₈ is H.

In other embodiments, R₅ and R₆ are each independently H, halo, C₁-C₆alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; R₇ is 3-6membered cycloalkyl or phenyl, wherein said 3-6 membered cycloalkyl orphenyl is substituted with 1-3 substituents selected from a groupconsisting of C₁-C₆ alkoxy, CN, and —C(O)NH₂; and R₈ is H. In otherembodiments, R₅ and R₆ are each independently H, halo, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; R₇ is 3-6 memberedcycloalkyl, wherein said 3-6 membered cycloalkyl is substituted with 1-3substituents selected from a group consisting of C₁-C₆ alkoxy, CN, and—C(O)NH₂; and R₈ is H. In other embodiments, R₅ and R₆ are eachindependently H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy; R₇ is cyclohexyl, wherein said cyclohexyl issubstituted with 1-3 substituents selected from a group consisting ofC₁-C₆ alkoxy, CN, and —C(O)NH₂; and R₈ is H. In other embodiments, R₅and R₆ are each independently H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl,C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; R₇ is phenyl, wherein said phenyl issubstituted with 1-3 substituents selected from a group consisting ofC₁-C₆ alkoxy, CN, and —C(O)NH₂; and R₈ is H.

In other embodiments, R₅ is H, halo, or C₁-C₆ alkyl; R₆ is H; R₇ is 3-6membered cycloalkyl or phenyl, wherein said 3-6 membered cycloalkyl orphenyl is substituted with 1-3 substituents selected from a groupconsisting of C₁-C₆ alkoxy, CN, and —C(O)NH₂; and R₈ is H. In otherembodiments, R₅ is H, halo, or C₁-C₆ alkyl; R₆ is H; R₇ is 3-6 memberedcycloalkyl, wherein said 3-6 membered cycloalkyl is substituted with 1-3substituents selected from a group consisting of C₁-C₆ alkoxy, CN, and—C(O)NH₂; and R₈ is H. In other embodiments, R₅ is H, halo, or C₁-C₆alkyl; R₆ is H; R₇ is cyclohexyl, wherein said cyclohexyl is substitutedwith 1-3 substituents selected from a group consisting of C₁-C₆ alkoxy,CN, and —C(O)NH₂; and R₈ is H. In other embodiments, R₅ is H, halo, orC₁-C₆ alkyl; R₆ is H; R₇ is phenyl, wherein said phenyl is substitutedwith 1-3 substituents selected from a group consisting of C₁-C₆ alkoxy,CN, and —C(O)NH₂; and R₈ is H. In other embodiments, R₅ is H, F, or CH₃;R₆ is H; R₇ is

and R₈ is H. In other embodiments, R₅ is H, F, or CH₃; R₆ is H; R₇ is

and R₈ is H. In other embodiments, R₅ is H, F, or CH₃; R₆ is H; R₇ is

and R₈ is H. In other embodiments, R₅ is H, F, or CH₃; R₆ is H; R₇ is

and R₈ is H. In other embodiments, R₅ is H, F, or CH₃; R₆ is H; R₇ is

and R₈ is H. In other embodiments, R₅ is H, F, or CH₃; R₆ is H; R₇ is

and R₈ is H. In other embodiments, R₅ is H, F, or CH₃; R₆ is H; R₇ is

and R₈ is H. In other embodiments, R₅ is H, F, or CH₃; R₆ is H; R₇ is

and R₈ is H. In other embodiments, R₅ is H, F, or CH₃; R₆ is H; R₇ is

and R₈ is H. In other embodiments, R₅ is H, F, or CH₃; R₆ is H; R₇ is

and R₈ is H.

In some embodiments, the invention relates to a compound of formula (I),or a pharmaceutically acceptable salt thereof, wherein R₅ is H, halo,C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; R₆ andR₇, together with the carbon atoms to which they are attached, form aring of formula

and R₈ is H. In other embodiments, R₅ is H or halo; R₆ and R₇, togetherwith the carbon atoms to which they are attached, form a ring of formula

and R₈ is H. In other embodiments, R₅ is H or halo; R₆ and R₇, togetherwith the carbon atoms to which they are attached, form a ring of formula

and R₈ is H. In other embodiments, R_(s) is H or F; R₆ and R₇, togetherwith the carbon atoms to which they are attached, form a ring of formula

and R₈ is H.

In some embodiments, the invention relates to a compound of formula (I),or a pharmaceutically acceptable salt thereof, wherein R₉ is halo, C₁-C₆alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. In otherembodiments, R₉ is H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy. In other embodiments, R₉ is H, halo, C₁-C₆ haloalkyl,C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₉ is H, halo,C₁-C₆ alkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₉is H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or C₁-C₆ haloalkoxy. In otherembodiments, R₉ is H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or C₁-C₆alkoxy. In other embodiments, R₉ is C₁-C₆ alkoxy. In other embodiments,R₉ is OCH₃, OC(¹H)₃, or OCD₃. In other embodiments, R₉ is OCH₃. In otherembodiments, R₉ is OC(¹H)₃. In other embodiments, R₉ is OCD₃.

In some embodiments, the invention relates to a compound of formula (I),or a pharmaceutically acceptable salt thereof, wherein R₁₀ is H. Inother embodiments, R₁₀ is halo. In other embodiments, R₁₀ is F.

In some embodiments, the invention relates to a compound of formula (I),or a pharmaceutically acceptable salt thereof, wherein R₁₁ is halo,C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. Inother embodiments, R₁₁ is H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy,or C₁-C₆ haloalkoxy. In other embodiments, R₁₁ is H, halo, C₁-C₆haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₁₁is H, halo, C₁-C₆ alkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. In otherembodiments, R₁₁ is H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or C₁-C₆haloalkoxy. In other embodiments, R₁₁ is H, halo, C₁-C₆ alkyl, C₁-C₆haloalkyl, or C₁-C₆ alkoxy. In other embodiments, R₁₁ is C₁-C₆haloalkoxy. In other embodiments, R₁₁ is OCF₃.

In some embodiments, the invention relates to a compound of formula (I),or a pharmaceutically acceptable salt thereof, wherein R₁₂ is H.

In some embodiments, the invention relates to a compound of formula (I),or a pharmaceutically acceptable salt thereof, wherein R₁₃ is H.

In some embodiments, the invention relates to a compound of formula (I),i.e., the compound in non-salt form.

In one aspect, the invention relates to a compound of formula (II)

or a pharmaceutically acceptable salt thereof, wherein:

each R is independently H or C₁-C₆ alkyl;

R_(1b) is H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆haloalkoxy;

R_(3b) is H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆haloalkoxy;

R_(4b) is H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆haloalkoxy;

R₅, R₆, R₇, and R₈ are defined as follows:

(i) R₅, R₆, and R₇ are each independently H, halo, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; and R₈ is C₁-C₆ alkyl;

(ii) R₅ is W—(CH₂)_(n)—R_(z), C₁-C₆ alkylsulfanyl, —O—(CH₂)_(p)—R_(w),or —O—(CH₂)_(p)—N(C₁-C₆ alkyl)₂; R₆ and R₇ are each independently H,halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy;and R₈ is H;

(iii) R₅ and R₆ are each independently H, halo, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; R₇ is W—(CH₂)_(n)—R_(z),—C≡C—R_(x), or 3-6 membered cycloalkyl or phenyl, wherein said 3-6membered cycloalkyl or phenyl is substituted with 1-3 substituentsselected from a group consisting of C₁-C₆ alkoxy, CN, and —C(O)NH₂; andR₈ is H; or

(iv) R_(s) is H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy; R₆ and R₇, together with the carbon atoms to whichthey are attached, form a ring of formula

and R₈ is H;

R₉, R₁₀, R₁₁, R₁₂, and R₁₃ are each independently H, halo, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy;

each R₁₄ is independently H, halo, C₁-C₄ alkyl, or C₁-C₄ haloalkyl;

each W is independently O or a single bond;

R_(x) is C₁-C₆ alkyl or 3-6 membered cycloalkyl, wherein said 3-6membered cycloalkyl may be unsubstituted or may be substituted with 1-3substituents selected from a group consisting of halo, C₁-C₆ alkyl, andC₁-C₆ haloalkyl;

each R_(w) is independently 3-6 membered cycloalkyl, phenyl, or 5-6membered heteroaryl, wherein said 3-6 membered cycloalkyl, phenyl, or5-6 membered heteroaryl may be unsubstituted or may be substituted with1-3 substituents selected from a group consisting of halo, C₁-C₆ alkyl,and C₁-C₆ haloalkyl;

R_(z) is 3-6 membered heterocyclyl, 7-8 membered cycloalkyl, or 4-8membered cycloalkenyl, wherein said 3-6 membered heterocyclyl, 7-8membered cycloalkyl, or 4-8 membered cycloalkenyl may be unsubstitutedor may be substituted with 1-3 substituents selected from a groupconsisting of halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, and C₁-C₆ alkoxy, orwherein 2 substituents together with the atom to which they are attachedform a 5-6 membered heterocyclyl ring;

n is 0 or 1; and

p is 2 or 3.

In some embodiments, the invention relates to a compound of formula(II), or a pharmaceutically acceptable salt thereof, wherein each R isH. In other embodiments, each R is independently C₁-C₆ alkyl.

In some embodiments, the invention relates to a compound of formula(II), or a pharmaceutically acceptable salt thereof, wherein R_(3a) andR_(4a) are each H.

In some embodiments, the invention relates to a compound of formula(II), or a pharmaceutically acceptable salt thereof, wherein R_(1b),R_(3b), and R_(4b) are each H.

In some embodiments, the invention relates to a compound of formula(II), or a pharmaceutically acceptable salt thereof, wherein R₅, R₆, andR₇ are each independently H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆alkoxy, or C₁-C₆ haloalkoxy; and R_(s) is C₁-C₆ alkyl. In otherembodiments, R_(s) is H; R₆ is C₁-C₆ haloalkyl; R₇ is H; and R_(s) isC₁-C₆ alkyl. In other embodiments, R_(s) is H; R₆ is CF₃; R₇ is H; andR₈ is CH₃.

In some embodiments, the invention relates to a compound of formula(II), or a pharmaceutically acceptable salt thereof, wherein R₅ isW—(CH₂)_(n)—R_(z), C₁-C₆ alkylsulfanyl, —O—(CH₂)_(p)—R_(w), or—O—(CH₂)_(p)—N(C₁-C₆ alkyl)₂; R₆ and R₇ are each independently H, halo,C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; andR_(s) is H. In other embodiments, R₅ is W—(CH₂)_(n)—R_(z); R₆ and R₇ areeach independently H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy,or C₁-C₆ haloalkoxy; and R_(s) is H. In other embodiments, R_(s) isO—R_(z), and R_(z) is 3-6 membered heterocyclyl, wherein said 3-6membered heterocyclyl may be unsubstituted or may be substituted with1-3 substituents selected from a group consisting of halo, C₁-C₆ alkyl,C₁-C₆ haloalkyl, and C₁-C₆ alkoxy; R₆ is C₁-C₆ haloalkyl; R₇ is H; andR₈ is H. In other embodiments, R_(s) is O—R_(z), and R_(z) is 3-6membered heterocyclyl; R₆ is C₁-C₆ haloalkyl; R₇ is H; and R₈ is H. Inother embodiments, R_(s) is O—R_(z), and R_(z) is oxetanyl ortetrahydrofuranyl; R₆ is C₁-C₆ haloalkyl; R₇ is H; and R₈ is H. In otherembodiments, R₈ is C₁-C₆ alkylsulfanyl; R₆ and R₇ are each independentlyH, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆haloalkoxy; and R_(s) is H. In other embodiments, R_(s) is C₁-C₆alkylsulfanyl; R₆ is C₁-C₆ haloalkyl; R₇ is H; and R_(s) is H. In otherembodiments, R_(s) is —O—(CH₂)_(p)—R_(w); R₆ and R₇ are eachindependently H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy; and R_(s) is H. In other embodiments, R_(s) is—O—(CH₂)_(p)—R_(w); R₆ is C₁-C₆ haloalkyl; R₇ is H; and R₈ is H. Inother embodiments, R_(s) is —O—(CH₂)_(p)—R_(w), and R_(w) is 3-6membered cycloalkyl, wherein said 3-6 membered cycloalkyl may beunsubstituted or may be substituted with 1-3 substituents selected froma group consisting of halo, C₁-C₆ alkyl, and C₁-C₆ haloalkyl; R₆ isC₁-C₆ haloalkyl; R₇ is H; and R_(s) is H. In other embodiments, R_(s) is—O—(CH₂)_(p)—R_(w), and R_(w) is 3-6 membered cycloalkyl; R₆ is C₁-C₆haloalkyl; R₇ is H; and R₈ is H. In other embodiments, R_(s) is—O—(CH₂)₂—R_(w), and R_(w) is 3-6 membered cycloalkyl; R₆ is C₁-C₆haloalkyl; R₇ is H; and R_(s) is H. In other embodiments, R_(s) is—O—(CH₂)_(p)—N(C₁-C₆ alkyl)₂; R₆ and R₇ are each independently H, halo,C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; and R₈is H. In other embodiments, R_(s) is —O—(CH₂)_(p)—N(CH₃)₂; R₆ is C₁-C₆haloalkyl; R₇ is H; and R₈ is H. In other embodiments, R_(s) is—O—(CH₂)₂—N(C₁-C₆ alkyl)₂; R₆ is C₁-C₆ haloalkyl; R₇ is H; and R₈ is H.In other embodiments, R₅ is

SCH₃,

or O(CH₂)₂N(CH₃)₂; R₆ is CF₃; R₇ is H; and R₈ is H. In otherembodiments, R₅ is

R₆ is CF₃; R₇ is H; and R₈ is H. In other embodiments, R_(s) is SCH₃; R₆is CF₃; R₇ is H; and R₈ is H. In other embodiments, R₅ is

is CF₃; R₇ is H; and R₈ is H. In other embodiments, R₅ isO(CH₂)₂N(CH₃)₂; R₆ is CF₃; R₇ is H; and R_(s) is H.

In some embodiments, the invention relates to a compound of formula (I)or (II), or a pharmaceutically acceptable salt thereof, wherein R₅ andR₆ are each independently H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆alkoxy, or C₁-C₆ haloalkoxy; R₇ is W—(CH₂)_(n)—R_(z), —C≡C—R_(x), or 3-6membered cycloalkyl or phenyl, wherein said 3-6 membered cycloalkyl orphenyl is substituted with 1-3 substituents selected from a groupconsisting of C₁-C₆ alkoxy, CN, and —C(O)NH₂; and R₈ is H. In otherembodiments, R₅ and R₆ are each independently H, halo, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; R₇ isW—(CH₂)_(n)—R_(z); and R₈ is H. In other embodiments, R₅ and R₆ are eachindependently H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy; R₇ is W—R_(z); and R₈ is H. In other embodiments, R₅and R₆ are each independently H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl,C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; R₇ is R_(z); and R₈ is H. In otherembodiments, R₅ and R₆ are each independently H, halo, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; R₇ is R_(z), andR_(z) is 3-6 membered heterocyclyl, wherein said 3-6 memberedheterocyclyl may be unsubstituted or may be substituted with 1-3substituents selected from a group consisting of halo, C₁-C₆ alkyl,C₁-C₆ haloalkyl, and C₁-C₆ alkoxy, or wherein 2 substituents togetherwith the atom to which they are attached form a 5-6 memberedheterocyclyl ring; and R₈ is H. In other embodiments, R₅ and R₆ are eachindependently H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy; R₇ is R_(z), and R_(z) is 3-6 membered heterocyclyl,wherein said 3-6 membered heterocyclyl may be unsubstituted or may besubstituted with 1-3 substituents selected from a group consisting ofhalo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, and C₁-C₆ alkoxy; and R₈ is H. Inother embodiments, R₅ and R₆ are each independently H, halo, C₁-C₆alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; R₇ is R_(z),and R_(z) is 5-6 membered heterocyclyl, wherein said 5-6 memberedheterocyclyl may be unsubstituted or may be substituted with 1-3substituents selected from a group consisting of halo, C₁-C₆ alkyl,C₁-C₆ haloalkyl, and C₁-C₆ alkoxy; and R₈ is H. In other embodiments, R₅and R₆ are each independently H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl,C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; R₇ is R_(z), and R_(z) is 5-6membered heterocyclyl; and R₈ is H. In other embodiments, R₅ and R₆ areeach independently H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy,or C₁-C₆ haloalkoxy; R₇ is R_(z), and R_(z) is 5-6 memberedheterocycloalkyl, wherein said 5-6 membered heterocycloalkyl may beunsubstituted or may be substituted with 1-3 substituents selected froma group consisting of halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, and C₁-C₆alkoxy; and R₈ is H. In other embodiments, R₅ and R₆ are eachindependently H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy; R₇ is R_(z), and R_(z) is 5-6 memberedheterocycloalkyl; and R₈ is H. In other embodiments, R₅ and R₆ are eachindependently H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy; R₇ is R_(z), and R_(z) is tetrahydropyran-4-yl ortetrahydrofuran-3-yl, wherein said tetrahydropyran-4-yl ortetrahydrofuran-3-yl may be unsubstituted or may be substituted with 1-3substituents selected from a group consisting of halo, C₁-C₆ alkyl,C₁-C₆ haloalkyl, and C₁-C₆ alkoxy; and R₈ is H. In other embodiments, R₅and R₆ are each independently H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl,C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; R₇ is R_(z), and R_(z) istetrahydropyran-4-yl or tetrahydrofuran-3-yl; and R₈ is H. In otherembodiments, R₅ and R₆ are each independently H, halo, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; R₇ is R_(z), andR_(z) is 5-6 membered heterocycloalkenyl, wherein said 5-6 memberedheterocycloalkenyl may be unsubstituted or may be substituted with 1-3substituents selected from a group consisting of halo, C₁-C₆ alkyl,C₁-C₆ haloalkyl, and C₁-C₆ alkoxy; and R₈ is H. In other embodiments, R₅and R₆ are each independently H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl,C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; R₇ is R_(z), and R_(z) is 5-6membered heterocycloalkenyl; and R₈ is H. In other embodiments, R₅ andR₆ are each independently H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆alkoxy, or C₁-C₆ haloalkoxy; R₇ is R_(z), and R_(z) is3,4-dihydropyran-5-yl, 3,6-dihydropyran-4-yl, 2,5-dihydrofuran-3-yl, or2,3-dihydrofuran-4-yl, wherein said 3,4-dihydropyran-5-yl,3,6-dihydropyran-4-yl, 2,5-dihydrofuran-3-yl, or 2,3-dihydrofuran-4-ylmay be unsubstituted or may be substituted with 1-3 substituentsselected from a group consisting of halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl,and C₁-C₆ alkoxy; and R₈ is H. In other embodiments, R₅ and R₆ are eachindependently H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy; R₇ is R_(z), and R_(z) is 3,4-dihydropyran-5-yl,3,6-dihydropyran-4-yl, 2,5-dihydrofuran-3-yl, or 2,3-dihydrofuran-4-yl;and R₈ is H. In other embodiments, R₅ and R₆ are each independently H,halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy;R₇ is R_(z), and R_(z) is 7-8 membered cycloalkyl, wherein said 7-8membered cycloalkyl may be unsubstituted or may be substituted with 1-3substituents selected from a group consisting of halo, C₁-C₆ alkyl,C₁-C₆ haloalkyl, and C₁-C₆ alkoxy, or wherein 2 substituents togetherwith the atom to which they are attached form a 5-6 memberedheterocyclyl ring; and R₈ is H. In other embodiments, R₅ and R₆ are eachindependently H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy; R₇ is R_(z), and R_(z) is 7-8 membered cycloalkyl; andR₈ is H. In other embodiments, R₅ and R₆ are each independently H, halo,C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; R₇ isR_(z), and R_(z) is 4-8 membered cycloalkenyl, wherein said 4-8 memberedcycloalkenyl may be unsubstituted or may be substituted with 1-3substituents selected from a group consisting of halo, C₁-C₆ alkyl,C₁-C₆ haloalkyl, and C₁-C₆ alkoxy, or wherein 2 substituents togetherwith the atom to which they are attached form a 5-6 memberedheterocyclyl ring; and R₈ is H. In other embodiments, R₅ and R₆ are eachindependently H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy; R₇ is R_(z), and R_(z) is 5-6 membered cycloalkenyl,wherein said 5-6 membered cycloalkenyl may be unsubstituted or may besubstituted with 1-3 substituents selected from a group consisting ofhalo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, and C₁-C₆ alkoxy, or wherein 2substituents together with the atom to which they are attached form a5-6 membered heterocyclyl ring; and R₈ is H. In other embodiments, R₅and R₆ are each independently H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl,C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; R₇ is R_(z), and R_(z) is 5-6membered cycloalkenyl, wherein said 5-6 membered cycloalkenyl may beunsubstituted or may be substituted with 1-3 substituents selected froma group consisting of halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, and C₁-C₆alkoxy; and R₈ is H. In other embodiments, R₅ and R₆ are eachindependently H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy; R₇ is R_(z), and R_(z) is 5-6 membered cycloalkenyl;and R₈ is H. In other embodiments, R₅ and R₆ are each independently H,halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy;R₇ is R_(z), and R_(z) is cyclohexen-1-yl or cyclopenten-1-yl, whereinsaid cyclohexen-1-yl or cyclopenten-1-yl may be unsubstituted or may besubstituted with 1-3 substituents selected from a group consisting ofhalo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, and C₁-C₆ alkoxy, or wherein 2substituents together with the atom to which they are attached form a5-6 membered heterocyclyl ring; and R₈ is H. In other embodiments, R₅and R₆ are each independently H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl,C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; R₇ is R_(z), and R_(z) iscyclohexen-1-yl or cyclopenten-1-yl, wherein said cyclohexen-1-yl orcyclopenten-1-yl may be unsubstituted or may be substituted with 1-3substituents selected from a group consisting of halo, C₁-C₆ alkyl,C₁-C₆ haloalkyl, and C₁-C₆ alkoxy; and R₈ is H. In other embodiments, R₅and R₆ are each independently H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl,C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; R₇ is R_(z), and R_(z) iscyclohexen-1-yl or cyclopenten-1-yl; and R₈ is H. In other embodiments,R₅ and R₆ are each independently H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl,C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; R₇ is O—R_(z); and R₈ is H. In otherembodiments, R₅ and R₆ are each independently H, halo, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; R₇ is O—R_(z), andR_(z) is R_(z) is 4-8 membered cycloalkenyl, wherein said 4-8 memberedcycloalkenyl may be unsubstituted or may be substituted with 1-3substituents selected from a group consisting of halo, C₁-C₆ alkyl,C₁-C₆ haloalkyl, and C₁-C₆ alkoxy; and R₈ is H. In other embodiments, R₅and R₆ are each independently H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl,C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; R₇ is O—R_(z), and R_(z) is R_(z) iscyclobutenyl, wherein said cyclobutenyl may be unsubstituted or may besubstituted with 1-3 substituents selected from a group consisting ofhalo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, and C₁-C₆ alkoxy; and R₈ is H.

In other embodiments, R₅ is H, halo, or C₁-C₆ alkyl; R₆ is H; R₇ isW—(CH₂)_(n)—R_(z); and R₈ is H. In other embodiments, R₅ is H, halo, orC₁-C₆ alkyl; R₆ is H; R₇ is W—R_(z); and R₈ is H. In other embodiments,R₅ is H, halo, or C₁-C₆ alkyl; R₆ is H; R₇ is R_(z); and R₈ is H. Inother embodiments, R₅ is H, halo, or C₁-C₆ alkyl; R₆ is H; R₇ is R_(z),and R_(z) is 3-6 membered heterocyclyl, wherein said 3-6 memberedheterocyclyl may be unsubstituted or may be substituted with 1-3substituents selected from a group consisting of halo, C₁-C₆ alkyl,C₁-C₆ haloalkyl, and C₁-C₆ alkoxy, or wherein 2 substituents togetherwith the atom to which they are attached form a 5-6 memberedheterocyclyl ring; and R₈ is H. In other embodiments, R₅ is H, halo, orC₁-C₆ alkyl; R₆ is H; R₇ is R_(z), and R_(z) is 3-6 memberedheterocyclyl, wherein said 3-6 membered heterocyclyl may beunsubstituted or may be substituted with 1-3 substituents selected froma group consisting of halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, and C₁-C₆alkoxy; and R₈ is H. In other embodiments, R₅ is H, halo, or C₁-C₆alkyl; R₆ is H; R₇ is R_(z), and R_(z) is 5-6 membered heterocyclyl,wherein said 5-6 membered heterocyclyl may be unsubstituted or may besubstituted with 1-3 substituents selected from a group consisting ofhalo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, and C₁-C₆ alkoxy; and R₈ is H. Inother embodiments, R₈ is H, halo, or C₁-C₆ alkyl; R₆ is H; R₇ is R_(z),and R_(z) is 5-6 membered heterocyclyl; and R₈ is H. In otherembodiments, R₅ is H, halo, or C₁-C₆ alkyl; R₆ is H; R₇ is R_(z), andR_(z) is 5-6 membered heterocycloalkyl, wherein said 5-6 memberedheterocycloalkyl may be unsubstituted or may be substituted with 1-3substituents selected from a group consisting of halo, C₁-C₆ alkyl,C₁-C₆ haloalkyl, and C₁-C₆ alkoxy; and R₈ is H. In other embodiments, R₅is H, halo, or C₁-C₆ alkyl; R₆ is H; R₇ is R_(z), and R_(z) is 5-6membered heterocycloalkyl; and R_(s) is H. In other embodiments, R₅ isH, halo, or C₁-C₆ alkyl; R₆ is H; R₇ is R_(z), and R_(z) istetrahydropyran-4-yl or tetrahydrofuran-3-yl, wherein saidtetrahydropyran-4-yl or tetrahydrofuran-3-yl may be unsubstituted or maybe substituted with 1-3 substituents selected from a group consisting ofhalo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, and C₁-C₆ alkoxy; and R₈ is H. Inother embodiments, R₅ is H, halo, or C₁-C₆ alkyl; R₆ is H; R₇ is R_(z),and R_(z) is tetrahydropyran-4-yl or tetrahydrofuran-3-yl; and R₈ is H.In other embodiments, R₅ is H, halo, or C₁-C₆ alkyl; R₆ is H; R₇ isR_(z), and R_(z) is 5-6 membered heterocycloalkenyl, wherein said 5-6membered heterocycloalkenyl may be unsubstituted or may be substitutedwith 1-3 substituents selected from a group consisting of halo, C₁-C₆alkyl, C₁-C₆ haloalkyl, and C₁-C₆ alkoxy; and R_(s) is H. In otherembodiments, R₅ is H, halo, or C₁-C₆ alkyl; R₆ is H; R₇ is R_(z), andR_(z) is 5-6 membered heterocycloalkenyl; and R₈ is H. In otherembodiments, R₅ is H, halo, or C₁-C₆ alkyl; R₆ is H; R₇ is R_(z), andR_(z) is 3,4-dihydropyran-5-yl, 3,6-dihydropyran-4-yl,2,5-dihydrofuran-3-yl, or 2,3-dihydrofuran-4-yl, wherein said3,4-dihydropyran-5-yl, 3,6-dihydropyran-4-yl, 2,5-dihydrofuran-3-yl, or2,3-dihydrofuran-4-yl may be unsubstituted or may be substituted with1-3 substituents selected from a group consisting of halo, C₁-C₆ alkyl,C₁-C₆ haloalkyl, and C₁-C₆ alkoxy; and R₈ is H. In other embodiments, R₅is H, halo, or C₁-C₆ alkyl; R₆ is H; R₇ is R_(z), and R_(z) is3,4-dihydropyran-5-yl, 3,6-dihydropyran-4-yl, 2,5-dihydrofuran-3-yl, or2,3-dihydrofuran-4-yl; and R₈ is H. In other embodiments, R₅ is H, halo,or C₁-C₆ alkyl; R₆ is H; R₇ is R_(z), and R_(z) is 7-8 memberedcycloalkyl, wherein said 7-8 membered cycloalkyl may be unsubstituted ormay be substituted with 1-3 substituents selected from a groupconsisting of halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, and C₁-C₆ alkoxy, orwherein 2 substituents together with the atom to which they are attachedform a 5-6 membered heterocyclyl ring; and R₈ is H. In otherembodiments, R₅ is H, halo, or C₁-C₆ alkyl; R₆ is H; R₇ is R_(z), andR_(z) is 7-8 membered cycloalkyl; and R_(s) is H. In other embodiments,R₅ is H, halo, or C₁-C₆ alkyl; R₆ is H; R₇ is R_(z), and R_(z) is 4-8membered cycloalkenyl, wherein said 4-8 membered cycloalkenyl may beunsubstituted or may be substituted with 1-3 substituents selected froma group consisting of halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, and C₁-C₆alkoxy, or wherein 2 substituents together with the atom to which theyare attached form a 5-6 membered heterocyclyl ring; and R₈ is H. Inother embodiments, R₅ is H, halo, or C₁-C₆ alkyl; R₆ is H; R₇ is R_(z),and R_(z) is 5-6 membered cycloalkenyl, wherein said 5-6 memberedcycloalkenyl may be unsubstituted or may be substituted with 1-3substituents selected from a group consisting of halo, C₁-C₆ alkyl,C₁-C₆ haloalkyl, and C₁-C₆ alkoxy, or wherein 2 substituents togetherwith the atom to which they are attached form a 5-6 memberedheterocyclyl ring; and R₈ is H. In other embodiments, R₅ is H, halo, orC₁-C₆ alkyl; R₆ is H; R₇ is R_(z), and R_(z) is 5-6 memberedcycloalkenyl, wherein said 5-6 membered cycloalkenyl may beunsubstituted or may be substituted with 1-3 substituents selected froma group consisting of halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, and C₁-C₆alkoxy; and R₈ is H. In other embodiments, R₅ is H, halo, or C₁-C₆alkyl; R₆ is H; R₇ is R_(z), and R_(z) is 5-6 membered cycloalkenyl; andR₈ is H. In other embodiments, R₅ is H, halo, or C₁-C₆ alkyl; R₆ is H;R₇ is R_(z), and R_(z) is cyclohexen-1-yl or cyclopenten-1-yl, whereinsaid cyclohexen-1-yl or cyclopenten-1-yl may be unsubstituted or may besubstituted with 1-3 substituents selected from a group consisting ofhalo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, and C₁-C₆ alkoxy, or wherein 2substituents together with the atom to which they are attached form a5-6 membered heterocyclyl ring; and R_(s) is H. In other embodiments, R₅is H, halo, or C₁-C₆ alkyl; R₆ is H; R₇ is R_(z), and R_(z) iscyclohexen-1-yl or cyclopenten-1-yl, wherein said cyclohexen-1-yl orcyclopenten-1-yl may be unsubstituted or may be substituted with 1-3substituents selected from a group consisting of halo, C₁-C₆ alkyl,C₁-C₆ haloalkyl, and C₁-C₆ alkoxy; and R_(s) is H. In other embodiments,R₅ is H, halo, or C₁-C₆ alkyl; R₆ is H; R₇ is R_(z), and R_(z) iscyclohexen-1-yl or cyclopenten-1-yl; and R₈ is H. In other embodiments,R_(s) is H, halo, or C₁-C₆ alkyl; R₆ is H; R₇ is O—R_(z); and R₈ is H.In other embodiments, R_(s) is H, halo, or C₁-C₆ alkyl; R₆ is H; R₇ isO—R_(z), and R_(z) is R_(z) is 4-8 membered cycloalkenyl, wherein said4-8 membered cycloalkenyl may be unsubstituted or may be substitutedwith 1-3 substituents selected from a group consisting of halo, C₁-C₆alkyl, C₁-C₆ haloalkyl, and C₁-C₆ alkoxy; and R₈ is H. In otherembodiments, R_(s) is H, halo, or C₁-C₆ alkyl; R₆ is H; R₇ is O—R_(z),and R_(z) is R_(z) is cyclobutenyl, wherein said cyclobutenyl may beunsubstituted or may be substituted with 1-3 substituents selected froma group consisting of halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, and C₁-C₆alkoxy; and R₈ is H.

In other embodiments, R₅ and R₆ are each independently H, halo, C₁-C₆alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; R₇ is—C≡C—R_(x); and R₈ is H. In other embodiments, R₅ and R₆ are eachindependently H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy; R₇ is —C≡C—R_(x), and R_(x) is C₁-C₆ alkyl; and R₈ isH. In other embodiments, R₅ and R₆ are each independently H, halo, C₁-C₆alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; R₇ is—C≡C—R_(x), and R_(x) is 3-6 membered cycloalkyl, wherein said 3-6membered cycloalkyl may be unsubstituted or may be substituted with 1-3substituents selected from a group consisting of halo; and R₈ is H. Inother embodiments, R₅ and R₆ are each independently H, halo, C₁-C₆alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; R₇ is—C≡C—R_(x), and R, is 3-6 membered cycloalkyl, wherein said 3-6 memberedcycloalkyl may be unsubstituted or may be substituted with 1-3substituents selected from a group consisting of halo; and R₈ is H. Inother embodiments, R₅ and R₆ are each independently H, halo, C₁-C₆alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; R₇ is—C≡C—R_(x), and R, is 3-6 membered cycloalkyl; and R₈ is H. In otherembodiments, R₅ and R₆ are each independently H, halo, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; R₇ is —C≡C—R_(x),and R_(x) is cyclopropyl or cyclobutyl; and R₈ is H.

In other embodiments, R_(s) is H, halo, or C₁-C₆ alkyl; R₆ is H; R₇ is—C≡C—R_(x); and R₈ is H. In other embodiments, R_(s) is H, halo, orC₁-C₆ alkyl; R₆ is H; R₇ is —C≡C—R_(x), and R, is C₁-C₆ alkyl; and R₈ isH. In other embodiments, R_(s) is H, halo, or C₁-C₆ alkyl; R₆ is H; R₇is —C≡C—R_(x), and R_(x) is 3-6 membered cycloalkyl, wherein said 3-6membered cycloalkyl may be unsubstituted or may be substituted with 1-3substituents selected from a group consisting of halo; and R_(s) is H.In other embodiments, R_(s) is H, halo, or C₁-C₆ alkyl; R₆ is H; R₇ is—C≡C—R_(x), and R_(x) is 3-6 membered cycloalkyl, wherein said 3-6membered cycloalkyl may be unsubstituted or may be substituted with 1-3substituents selected from a group consisting of halo; and R₈ is H. Inother embodiments, R_(s) is H, halo, or C₁-C₆ alkyl; R₆ is H; R₇ is—C≡C—R_(x), and R_(x) is 3-6 membered cycloalkyl; and R₈ is H. In otherembodiments, R_(s) is H, halo, or C₁-C₆ alkyl; R₆ is H; R₇ is—C≡C—R_(x), and R_(x) is cyclopropyl or cyclobutyl; and R₈ is H.

In other embodiments, R₅ and R₆ are each independently H, halo, C₁-C₆alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; R₇ is 3-6membered cycloalkyl or phenyl, wherein said 3-6 membered cycloalkyl orphenyl is substituted with 1-3 substituents selected from a groupconsisting of C₁-C₆ alkoxy, CN, and —C(O)NH₂; and R₈ is H. In otherembodiments, R₅ and R₆ are each independently H, halo, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; R₇ is 3-6 memberedcycloalkyl, wherein said 3-6 membered cycloalkyl is substituted with 1-3substituents selected from a group consisting of C₁-C₆ alkoxy, CN, and—C(O)NH₂; and R₈ is H. In other embodiments, R₅ and R₆ are eachindependently H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy; R₇ is cyclohexyl, wherein said cyclohexyl issubstituted with 1-3 substituents selected from a group consisting ofC₁-C₆ alkoxy, CN, and —C(O)NH₂; and R₈ is H. In other embodiments, R₅and R₆ are each independently H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl,C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; R₇ is phenyl, wherein said phenyl issubstituted with 1-3 substituents selected from a group consisting ofC₁-C₆ alkoxy, CN, and —C(O)NH₂; and R₈ is H.

In other embodiments, R_(s) is H, halo, or C₁-C₆ alkyl; R₆ is H; R₇ is3-6 membered cycloalkyl or phenyl, wherein said 3-6 membered cycloalkylor phenyl is substituted with 1-3 substituents selected from a groupconsisting of C₁-C₆ alkoxy, CN, and —C(O)NH₂; and R₈ is H. In otherembodiments, R_(s) is H, halo, or C₁-C₆ alkyl; R₆ is H; R₇ is 3-6membered cycloalkyl, wherein said 3-6 membered cycloalkyl is substitutedwith 1-3 substituents selected from a group consisting of C₁-C₆ alkoxy,CN, and —C(O)NH₂; and R₈ is H. In other embodiments, R_(s) is H, halo,or C₁-C₆ alkyl; R₆ is H; R₇ is cyclohexyl, wherein said cyclohexyl issubstituted with 1-3 substituents selected from a group consisting ofC₁-C₆ alkoxy, CN, and —C(O)NH₂; and R₈ is H. In other embodiments, R_(s)is H, halo, or C₁-C₆ alkyl; R₆ is H; R₇ is phenyl, wherein said phenylis substituted with 1-3 substituents selected from a group consisting ofC₁-C₆ alkoxy, CN, and —C(O)NH₂; and R₈ is H. In other embodiments, R_(s)is H, F, or CH₃; R₆ is H; R₇ is

and R₈ is H. In other embodiments, R₅ is H, F, or CH₃; R₆ is H; R₇ is

and R₈ is H. In other embodiments, R₅ is H, F, or CH₃; R₆ is H; R₇ is

and R₈ is H. In other embodiments, R₅ is H, F, or CH₃; R₆ is H; R₇ is

and R₈ is H. In other embodiments, R₅ is H, F, or CH₃; R₆ is R₇ is

and R₈ is H. In other embodiments, R_(s) is H, F, or CH₃; R₆ is H; R₇ is

and R₈ is H. In other embodiments, R₅ is H, F, or CH₃; R₆ is H; R₇ is

and R₈ is H. In other embodiments, R₅ is H, F, or CH₃; R₆ is H; R₇ is

and R₈ is H. In other embodiments, R₅ is H, F, or CH₃; R₆ is H; R₇ is

and R₈ is H. In other embodiments, R₅ is H, F, or CH₃; R₆ is H; R₇ is

and R₈ is H.

In some embodiments, the invention relates to a compound of formula(II), or a pharmaceutically acceptable salt thereof, wherein R₅ is H,halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy;R₆ and R₇, together with the carbon atoms to which they are attached,form a ring of formula

and R₈ is H. In other embodiments, R₅ is H or halo: R₆ and R₇, togetherwith the carbon atoms to which they are attached, form a ring of formula

and R₈ is H. In other embodiments, R₅ is H or halo; R₆ and R₇, togetherwith the carbon atoms to which they are attached, form a ring of formula

and R₈ is H. In other embodiments, R₅ is H or F; R₆ and R₇, togetherwith the carbon atoms to which they are attached, form a ring of formula

and R₈ is H.

In some embodiments, the invention relates to a compound of formula(II), or a pharmaceutically acceptable salt thereof, wherein R₉ is halo,C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. Inother embodiments, R₉ is H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy,or C₁-C₆ haloalkoxy. In other embodiments, R₉ is H, halo, C₁-C₆haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₉is H, halo, C₁-C₆ alkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. In otherembodiments, R₉ is H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or C₁-C₆haloalkoxy. In other embodiments, R₉ is H, halo, C₁-C₆ alkyl, C₁-C₆haloalkyl, or C₁-C₆ alkoxy. In other embodiments, R₉ is C₁-C₆ alkoxy. Inother embodiments, R₉ is OCH₃, OC(¹H)₃, or OCD₃. In other embodiments,R₉ is OCH₃. In other embodiments, R₉ is OC(¹H)₃. In other embodiments,R₉ is OCD₃.

In some embodiments, the invention relates to a compound of formula(II), or a pharmaceutically acceptable salt thereof, wherein R₁₀ is H.In other embodiments, R₁₀ is halo. In other embodiments, R₁₀ is F.

In some embodiments, the invention relates to a compound of formula(II), or a pharmaceutically acceptable salt thereof, wherein R₁₁ ishalo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy.In other embodiments, R₁₁ is H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₁₁ is H, halo, C₁-C₆haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R₁₁is H, halo, C₁-C₆ alkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. In otherembodiments, R₁₁ is H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or C₁-C₆haloalkoxy. In other embodiments, R₁₁ is H, halo, C₁-C₆ alkyl, C₁-C₆haloalkyl, or C₁-C₆ alkoxy. In other embodiments, R₁₁ is C₁-C₆haloalkoxy. In other embodiments, R₁₁ is OCF₃.

In some embodiments, the invention relates to a compound of formula(II), or a pharmaceutically acceptable salt thereof, wherein R₁₂ is H.

In some embodiments, the invention relates to a compound of formula(II), or a pharmaceutically acceptable salt thereof, wherein R₁₃ is H.

In some embodiments, the invention relates to a compound of formula(II), i.e., the compound in non-salt form.

In one aspect, the invention relates to a compound selected from Table Aor a pharmaceutically acceptable salt thereof. In other embodiments, theinvention relates to a compound selected from Table A, i.e., thecompound in non-salt form.

TABLE A Compound Numbers and Structures.

1

2

3

4

5

6

7

8

9

10

11

12

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

83

84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

100

101

102

103

104

105

106

107

114

115

116

117

118

119

120

121

122

123

124

125

126

127

128

129

130

131

132

133

134

135

136

137

138

139

140

141

142

143

144

145

146

147

148

149

150

151

152

153

154

155

156

157

158-a

158-b

159

160

161

162

163

164

165

166

167

168-a

168-b

169-a

169-b

170

171

172

173

174

175

176

177

178

179

180

181

182

183

184

185

186

187

188

189

190

191

192

193

194

195

196

197

198

199

200

201

202

203

204

205

206

207

208

209

210

211

212

213

214

215

216

217

218

219

220

221

222

223

224

225

226

227

228

229

230

231

232

233

234

235

236

237

238

239

240

241

242

243

244

245

246

247

248

249

255

256

253

254

82

250

252

81

258

108

110

111

251

112

13

14

15

16

17

113

257

In another aspect, the invention relates to a compound selected fromTable B or a pharmaceutically acceptable salt thereof. In otherembodiments, the invention relates to a compound selected from Table B,i.e., the compound in non-salt form.

TABLE B Compound Numbers and Structures.

259

260

261

262

263

264

265

266

267

268

269

270

271

272

273

274

275

276

277

278

279

280

281

282

283

284

285

286

287

288

289

290

291

292

293

294

295

296

297

298

299

300

301

302

303

304

305

306

307

308

309

310

311

312

313

314

315

316

317

318

319

320

321

322

323

324

325

326

327

328

329

330

331

332

333

334

335

336

337

338

339

340

341

342

343

344

345

346

347

348

349

350

351

352

353

354

355

356

357

358

359

360

361

362

363

364

365

366

367

368

369

370

371

372

373

374

375

376

377

378

379

380

381

382

383

109

In some embodiments, the invention relates to a compound selected fromTable C or a pharmaceutically acceptable salt thereof. In otherembodiments, the invention relates to a compound selected from Table C,i.e., the compound in non-salt form.

TABLE C Compound Numbers and Structures.

1001

1002

1003

1004

1005

1006

1007

1008

1009

1010

1011

1012

1013

1014

1015

1016

1017-a

1017-b

1018

1019

1020

1021

1022

1023

1024

1025

1026

1027

1028

1029

1030

1031

1032-a

1032-b

1033

1034

1035

1036

1037

1038

1039

In some embodiments, the invention relates to a compound selected fromTable D or a pharmaceutically acceptable salt thereof. In otherembodiments, the invention relates to a compound selected from Table D,i.e., the compound in non-salt form.

TABLE D Compound Numbers and Structures.

1040

1041

In some embodiments, the invention relates to a compound of formula

or a pharmaceutically acceptable salt thereof, wherein the compound hasthe relative stereochemistry of the first eluting diastereomer when amixture of the diastereomers is separated by HPLC Method B, as describedin Example 68. Such compound is considered to be a “compound of theinvention,” as that term is used herein.

In some embodiments, the invention relates to a compound of formula

or a pharmaceutically acceptable salt thereof, wherein the compound hasthe relative stereochemistry of the second eluting diastereomer when amixture of the diastereomers is separated by HPLC Method B, as describedin Example 68. Such compound is considered to be a “compound of theinvention,” as that term is used herein.

In some embodiments, the invention relates to a compound of formula

or a pharmaceutically acceptable salt thereof, wherein the compound hasthe relative stereochemistry of the first eluting diastereomer when amixture of the diastereomers is separated by HPLC Method B, as describedin Example 24. Such compound is considered to be a “compound of theinvention,” as that term is used herein.

In some embodiments, the invention relates to a compound of formula

or a pharmaceutically acceptable salt thereof, wherein the compound hasthe relative stereochemistry of the second eluting diastereomer when amixture of the diastereomers is separated by HPLC Method B, as describedin Example 24. Such compound is considered to be a “compound of theinvention,” as that term is used herein.

In some embodiments, the invention relates to a compound of formula

or a pharmaceutically acceptable salt thereof, wherein the compound hasthe relative stereochemistry of the first eluting diastereomer when amixture of the diastereomers is separated by HPLC Method B, as describedin Example 24. Such compound is considered to be a “compound of theinvention,” as that term is used herein.

In some embodiments, the invention relates to a compound of formula

or a pharmaceutically acceptable salt thereof, wherein the compound hasthe relative stereochemistry of the second eluting diastereomer when amixture of the diastereomers is separated by HPLC Method B, as describedin Example 24. Such compound is considered to be a “compound of theinvention,” as that term is used herein.

In some embodiments, the invention relates to a compound of formula (I),or a pharmaceutically acceptable salt thereof, wherein the compound hasformula

wherein the compound has the relative stereochemistry of the firsteluting diastereomer when a mixture of the diastereomers is separated byHPLC Method B, as described in Example 204.

In some embodiments, the invention relates to a compound of formula (I),or a pharmaceutically acceptable salt thereof, wherein the compound hasformula

wherein the compound has the relative stereochemistry of the secondeluting diastereomer when a mixture of the diastereomers is separated byHPLC Method B, as described in Example 204.

In some embodiments, the invention relates to a compound of formula (I),or a pharmaceutically acceptable salt thereof, wherein the compound hasformula

wherein the compound has the relative stereochemistry of the firsteluting diastereomer when a mixture of the diastereomers is separated byHPLC Method B, as described in Example 209.

In some embodiments, the invention relates to a compound of formula (I),or a pharmaceutically acceptable salt thereof, wherein the compound hasformula

wherein the compound has the relative stereochemistry of the secondeluting diastereomer when a mixture of the diastereomers is separated byHPLC Method B, as described in Example 209.

Salts, Compositions, Uses, Formulation, Administration and AdditionalAgents

Pharmaceutically acceptable salts and compositions

As discussed herein, the invention provides compounds, andpharmaceutically acceptable salts thereof, that are inhibitors ofvoltage-gated sodium channels, and thus the present compounds, andpharmaceutically acceptable salts thereof, are useful for the treatmentof diseases, disorders, and conditions including, but not limited tochronic pain, gut pain, neuropathic pain, musculoskeletal pain, acutepain, inflammatory pain, cancer pain, idiopathic pain, postsurgical pain(e.g., bunionectomy pain, herniorrhaphy pain or abdominoplasty pain),visceral pain, multiple sclerosis, Charcot-Marie-Tooth syndrome,incontinence, pathological cough, or cardiac arrhythmia. Accordingly, inanother aspect of the invention, pharmaceutical compositions areprovided, wherein these compositions comprise a compound as describedherein, or a pharmaceutically acceptable salt thereof, and optionallycomprise a pharmaceutically acceptable carrier, adjuvant or vehicle. Incertain embodiments, these compositions optionally further comprise oneor more additional therapeutic agents. In some embodiments, theadditional therapeutic agent is a sodium channel inhibitor.

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. A“pharmaceutically acceptable salt” of a compound of this inventionincludes any non-toxic salt that, upon administration to a recipient, iscapable of providing, either directly or indirectly, a compound of thisinvention or an inhibitorily active metabolite or residue thereof. Thesalt may be in pure form, in a mixture (e.g., solution, suspension, orcolloid) with one or more other substances, or in the form of a hydrate,solvate, or co-crystal. As used herein, the term “inhibitorily activemetabolite or residue thereof” means that a metabolite or residuethereof is also an inhibitor of a voltage-gated sodium channel.

Pharmaceutically acceptable salts are well known in the art. Forexample, S. M. Berge, et al. describe pharmaceutically acceptable saltsin detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporatedherein by reference. Pharmaceutically acceptable salts of the compoundof this invention include those derived from suitable inorganic andorganic acids and bases. Examples of pharmaceutically acceptable,nontoxic acid addition salts are salts of an amino group formed withinorganic acids such as hydrochloric acid, hydrobromic acid, phosphoricacid, sulfuric acid and perchloric acid or with organic acids such asacetic acid, oxalic acid, maleic acid, tartaric acid, citric acid,succinic acid or malonic acid or by using other methods used in the artsuch as ion exchange. Other pharmaceutically acceptable salts includeadipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate,bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptonate, glycerophosphate, gluconate,hemisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, stearate, succinate, sulfate, tartrate,thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and thelike. Salts derived from appropriate bases include alkali metal,alkaline earth metal, ammonium and N⁺(C₁₋₄ alkyl)₄ salts. Representativealkali or alkaline earth metal salts include sodium, lithium, potassium,calcium, magnesium, and the like. Further pharmaceutically acceptablesalts include, when appropriate, nontoxic ammonium, quaternary ammonium,and amine cations formed using counterions such as halide, hydroxide,carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and arylsulfonate.

As described herein, the pharmaceutically acceptable compositions of theinvention additionally comprise a pharmaceutically acceptable carrier,adjuvant, or vehicle, which, as used herein, includes any and allsolvents, diluents, or other liquid vehicle, dispersion or suspensionaids, surface active agents, isotonic agents, thickening or emulsifyingagents, preservatives, solid binders, lubricants and the like, as suitedto the particular dosage form desired. Remington's PharmaceuticalSciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton,Pa., 1980) discloses various carriers used in formulatingpharmaceutically acceptable compositions and known techniques for thepreparation thereof. Except insofar as any conventional carrier mediumis incompatible with the compounds of the invention, such as byproducing any undesirable biological effect or otherwise interacting ina deleterious manner with any other component(s) of the pharmaceuticallyacceptable composition, its use is contemplated to be within the scopeof this invention. Some examples of materials which can serve aspharmaceutically acceptable carriers include, but are not limited to,ion exchangers, alumina, aluminum stearate, lecithin, serum proteins,such as human serum albumin, buffer substances such as phosphates,glycine, sorbic acid, or potassium sorbate, partial glyceride mixturesof saturated vegetable fatty acids, water, salts or electrolytes, suchas protamine sulfate, disodium hydrogen phosphate, potassium hydrogenphosphate, sodium chloride, zinc salts, colloidal silica, magnesiumtrisilicate, polyvinyl pyrrolidone, polyacrylates, waxes,polyethylene-polyoxypropylene-block polymers, wool fat, sugars such aslactose, glucose and sucrose; starches such as corn starch and potatostarch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethyl cellulose and cellulose acetate; powdered tragacanth;malt; gelatin; talc; excipients such as cocoa butter and suppositorywaxes; oils such as peanut oil, cottonseed oil; safflower oil; sesameoil; olive oil; corn oil and soybean oil; glycols; such a propyleneglycol or polyethylene glycol; esters such as ethyl oleate and ethyllaurate; agar; buffering agents such as magnesium hydroxide and aluminumhydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer'ssolution; ethyl alcohol, and phosphate buffer solutions, as well asother non-toxic compatible lubricants such as sodium lauryl sulfate andmagnesium stearate, as well as coloring agents, releasing agents,coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the composition,according to the judgment of the formulator.

In another aspect, the invention features a pharmaceutical compositioncomprising a compound of the invention, or a pharmaceutically acceptablesalt thereof, and a pharmaceutically acceptable carrier.

In another aspect, the invention features a pharmaceutical compositioncomprising a therapeutically effective amount of a compound, or apharmaceutically acceptable salt thereof, and one or morepharmaceutically acceptable carriers or vehicles.

Uses of Compounds and Pharmaceutically Acceptable Salts and Compositions

In another aspect, the invention features a method of inhibiting avoltage-gated sodium channel in a subject comprising administering tothe subject a compound of the invention or a pharmaceutically acceptablesalt thereof or a pharmaceutical composition thereof. In another aspect,the voltage-gated sodium channel is Na_(V)1.8.

In yet another aspect, the invention features a method of treating orlessening the severity in a subject of chronic pain, gut pain,neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain,cancer pain, idiopathic pain, postsurgical pain (e.g., bunionectomypain, herniorrhaphy pain or abdominoplasty pain), visceral pain,multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence,pathological cough, or cardiac arrhythmia comprising administering aneffective amount of a compound of the invention, a pharmaceuticallyacceptable salt thereof or a pharmaceutical composition thereof.

In yet another aspect, the invention features a method of treating orlessening the severity in a subject of chronic pain, gut pain,neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain,cancer pain, idiopathic pain, postsurgical pain, herniorrhaphy pain,bunionectomy pain, multiple sclerosis, Charcot-Marie-Tooth syndrome,incontinence, or cardiac arrhythmia comprising administering aneffective amount of a compound of the invention, a pharmaceuticallyacceptable salt thereof or a pharmaceutical composition thereof.

In yet another aspect, the invention features a method of treating orlessening the severity in a subject of gut pain, wherein gut paincomprises inflammatory bowel disease pain, Crohn's disease pain orinterstitial cystitis pain wherein said method comprises administeringan effective amount of a compound of the invention, a pharmaceuticallyacceptable salt thereof or a pharmaceutical composition thereof.

In yet another aspect, the invention features a method of treating orlessening the severity in a subject of neuropathic pain comprisingadministering an effective amount of a compound of the invention, apharmaceutically acceptable salt thereof or a pharmaceutical compositionthereof. In some aspects, the neuropathic pain comprises post-herpeticneuralgia, small fiber neuropathy or idiopathic small-fiber neuropathy.As used herein, the phrase “idiopathic small-fiber neuropathy” shall beunderstood to include any small fiber neuropathy.

In yet another aspect, the invention features a method of treating orlessening the severity in a subject of neuropathic pain, whereinneuropathic pain comprises post-herpetic neuralgia, diabetic neuralgia,painful HIV-associated sensory neuropathy, trigeminal neuralgia, burningmouth syndrome, post-amputation pain, phantom pain, painful neuroma;traumatic neuroma; Morton's neuroma; nerve entrapment injury, spinalstenosis, carpal tunnel syndrome, radicular pain, sciatica pain; nerveavulsion injury, brachial plexus avulsion injury; complex regional painsyndrome, drug therapy induced neuralgia, cancer chemotherapy inducedneuralgia, anti-retroviral therapy induced neuralgia; post spinal cordinjury pain, small fiber neuropathy, idiopathic small-fiber neuropathy,idiopathic sensory neuropathy or trigeminal autonomic cephalalgiawherein said method comprises administering an effective amount of acompound of the invention, a pharmaceutically acceptable salt thereof ora pharmaceutical composition thereof.

In yet another aspect, the invention features a method of treating orlessening the severity in a subject of musculoskeletal pain comprisingadministering an effective amount of a compound of the invention, apharmaceutically acceptable salt thereof or a pharmaceutical compositionthereof. In some aspects, the musculoskeletal pain comprisesosteoarthritis pain.

In yet another aspect, the invention features a method of treating orlessening the severity in a subject of musculoskeletal pain, whereinmusculoskeletal pain comprises osteoarthritis pain, back pain, coldpain, burn pain or dental pain wherein said method comprisesadministering an effective amount of a compound of the invention, apharmaceutically acceptable salt thereof or a pharmaceutical compositionthereof.

In yet another aspect, the invention features a method of treating orlessening the severity in a subject of inflammatory pain, whereininflammatory pain comprises rheumatoid arthritis pain or vulvodyniawherein said method comprises administering an effective amount of acompound of the invention, a pharmaceutically acceptable salt thereof ora pharmaceutical composition thereof.

In yet another aspect, the invention features a method of treating orlessening the severity in a subject of inflammatory pain, whereininflammatory pain comprises rheumatoid arthritis pain wherein saidmethod comprises administering an effective amount of a compound of theinvention, a pharmaceutically acceptable salt thereof or apharmaceutical composition thereof.

In yet another aspect, the invention features a method of treating orlessening the severity in a subject of idiopathic pain, whereinidiopathic pain comprises fibromyalgia pain wherein said methodcomprises administering an effective amount of a compound of theinvention, a pharmaceutically acceptable salt thereof or apharmaceutical composition thereof.

In yet another aspect, the invention features a method of treating orlessening the severity in a subject of pathological cough wherein saidmethod comprises administering an effective amount of a compound of theinvention, a pharmaceutically acceptable salt thereof or apharmaceutical composition thereof.

In yet another aspect, the invention features a method of treating orlessening the severity in a subject of acute pain comprisingadministering an effective amount of a compound of the invention, apharmaceutically acceptable salt thereof or a pharmaceutical compositionthereof. In some aspects, the acute pain comprises acute post-operativepain.

In yet another aspect, the invention features a method of treating orlessening the severity in a subject of postsurgical pain (e.g.,herniorrhaphy pain, bunionectomy pain or abdominoplasty pain) comprisingadministering an effective amount of a compound of the invention, apharmaceutically acceptable salt thereof or a pharmaceutical compositionthereof.

In yet another aspect, the invention features a method of treating orlessening the severity in a subject of bunionectomy pain comprisingadministering an effective amount of a compound of the invention, apharmaceutically acceptable salt thereof or a pharmaceutical compositionthereof.

In yet another aspect, the invention features a method of treating orlessening the severity in a subject of herniorrhaphy pain comprisingadministering an effective amount of a compound of the invention, apharmaceutically acceptable salt thereof or a pharmaceutical compositionthereof.

In yet another aspect, the invention features a method of treating orlessening the severity in a subject of abdominoplasty pain comprisingadministering an effective amount of a compound of the invention, apharmaceutically acceptable salt thereof or a pharmaceutical compositionthereof.

In yet another aspect, the invention features a method of treating orlessening the severity in a subject of visceral pain comprisingadministering an effective amount of a compound of the invention, apharmaceutically acceptable salt thereof or a pharmaceutical compositionthereof. In some aspects, the visceral pain comprises visceral pain fromabdominoplasty.

In yet another aspect, the invention features a method wherein thesubject is treated with one or more additional therapeutic agentsadministered concurrently with, prior to, or subsequent to treatmentwith an effective amount of the compound, pharmaceutically acceptablesalt or pharmaceutical composition. In some embodiments, the additionaltherapeutic agent is a sodium channel inhibitor.

In another aspect, the invention features a method of inhibiting avoltage-gated sodium channel in a biological sample comprisingcontacting the biological sample with an effective amount of a compoundof the invention, a pharmaceutically acceptable salt thereof or apharmaceutical composition thereof. In another aspect, the voltage-gatedsodium channel is Na_(V)1.8.

In another aspect, the invention features a method of treating orlessening the severity in a subject of acute pain, chronic pain,neuropathic pain, inflammatory pain, arthritis, migraine, clusterheadaches, trigeminal neuralgia, herpetic neuralgia, general neuralgias,epilepsy, epilepsy conditions, neurodegenerative disorders, psychiatricdisorders, anxiety, depression, bipolar disorder, myotonia, arrhythmia,movement disorders, neuroendocrine disorders, ataxia, multiplesclerosis, irritable bowel syndrome, incontinence, pathological cough,visceral pain, osteoarthritis pain, postherpetic neuralgia, diabeticneuropathy, radicular pain, sciatica, back pain, head pain, neck pain,severe pain, intractable pain, nociceptive pain, breakthrough pain,postsurgical pain (e.g., herniorrhaphy pain, bunionectomy pain orabdominoplasty pain), cancer pain, stroke, cerebral ischemia, traumaticbrain injury, amyotrophic lateral sclerosis, stress induced angina,exercise induced angina, palpitations, hypertension, or abnormalgastro-intestinal motility, comprising administering an effective amountof a compound of the invention, a pharmaceutically acceptable saltthereof or a pharmaceutical composition thereof.

In another aspect, the invention features a method of treating orlessening the severity in a subject of femur cancer pain; non-malignantchronic bone pain; rheumatoid arthritis; osteoarthritis; spinalstenosis; neuropathic low back pain; myofascial pain syndrome;fibromyalgia; temporomandibular joint pain; chronic visceral pain,abdominal pain; pancreatic pain; IBS pain; chronic and acute headachepain; migraine; tension headache; cluster headaches; chronic and acuteneuropathic pain, post-herpetic neuralgia; diabetic neuropathy;HIV-associated neuropathy; trigeminal neuralgia; Charcot-Marie-Toothneuropathy; hereditary sensory neuropathy; peripheral nerve injury;painful neuromas; ectopic proximal and distal discharges; radiculopathy;chemotherapy induced neuropathic pain; radiotherapy-induced neuropathicpain; post-mastectomy pain; central pain; spinal cord injury pain;post-stroke pain; thalamic pain; complex regional pain syndrome; phantompain; intractable pain; acute pain, acute post-operative pain; acutemusculoskeletal pain; joint pain; mechanical low back pain; neck pain;tendonitis; injury pain; exercise pain; acute visceral pain;pyelonephritis; appendicitis; cholecystitis; intestinal obstruction;hernias; chest pain, cardiac pain; pelvic pain, renal colic pain, acuteobstetric pain, labor pain; cesarean section pain; acute inflammatorypain, burn pain, trauma pain; acute intermittent pain, endometriosis;acute herpes zoster pain; sickle cell anemia; acute pancreatitis;breakthrough pain; orofacial pain; sinusitis pain; dental pain; multiplesclerosis (MS) pain; pain in depression; leprosy pain; Behcet's diseasepain; adiposis dolorosa; phlebitic pain; Guillain-Barre pain; painfullegs and moving toes; Haglund syndrome; erythromelalgia pain; Fabry'sdisease pain; bladder and urogenital disease; urinary incontinence,pathological cough; hyperactive bladder; painful bladder syndrome;interstitial cystitis (IC); prostatitis; complex regional pain syndrome(CRPS), type I, complex regional pain syndrome (CRPS) type II;widespread pain, paroxysmal extreme pain, pruritus, tinnitus, orangina-induced pain, comprising administering an effective amount of acompound of the invention, a pharmaceutically acceptable salt thereof ora pharmaceutical composition thereof.

Compounds, Pharmaceutically Acceptable Salts, and Compositions for Use

In another aspect, the invention features a compound of the invention,or a pharmaceutically acceptable salt or pharmaceutical compositionthereof, for use as a medicament.

In another aspect, the invention features a compound of the invention,or a pharmaceutically acceptable salt or pharmaceutical compositionthereof, for use in a method of inhibiting a voltage-gated sodiumchannel in a subject. In another aspect, the voltage-gated sodiumchannel is Na_(V)1.8.

In another aspect, the invention features a compound of the invention,or a pharmaceutically acceptable salt or pharmaceutical compositionthereof, for use in a method of treating or lessening the severity in asubject of chronic pain, gut pain, neuropathic pain, musculoskeletalpain, acute pain, inflammatory pain, cancer pain, idiopathic pain,postsurgical pain (e.g., herniorrhaphy pain, bunionectomy pain orabdominoplasty pain), visceral pain, multiple sclerosis,Charcot-Marie-Tooth syndrome, incontinence, pathological cough, orcardiac arrhythmia.

In another aspect, the invention features a compound of the invention,or a pharmaceutically acceptable salt or pharmaceutical compositionthereof, for use in a method of treating or lessening the severity in asubject of chronic pain, gut pain, neuropathic pain, musculoskeletalpain, acute pain, inflammatory pain, cancer pain, idiopathic pain,postsurgical pain, herniorrhaphy pain, bunionectomy pain, multiplesclerosis, Charcot-Marie-Tooth syndrome, incontinence, or cardiacarrhythmia.

In another aspect, the invention features a compound of the invention,or a pharmaceutically acceptable salt or pharmaceutical compositionthereof, for use in a method of treating or lessening the severity in asubject of gut pain, wherein gut pain comprises inflammatory boweldisease pain, Crohn's disease pain or interstitial cystitis pain.

In another aspect, the invention features a compound of the invention,or a pharmaceutically acceptable salt or pharmaceutical compositionthereof, for use in a method of treating or lessening the severity in asubject of neuropathic pain. In some aspects, the neuropathic paincomprises post-herpetic neuralgia, small fiber neuropathy or idiopathicsmall-fiber neuropathy. As used herein, the phrase “idiopathicsmall-fiber neuropathy” shall be understood to include any small fiberneuropathy.

In another aspect, the invention features a compound of the invention,or a pharmaceutically acceptable salt or pharmaceutical compositionthereof, for use in a method of treating or lessening the severity in asubject of neuropathic pain, wherein neuropathic pain comprisespost-herpetic neuralgia, diabetic neuralgia, painful HIV-associatedsensory neuropathy, trigeminal neuralgia, burning mouth syndrome,post-amputation pain, phantom pain, painful neuroma; traumatic neuroma;Morton's neuroma; nerve entrapment injury, spinal stenosis, carpaltunnel syndrome, radicular pain, sciatica pain; nerve avulsion injury,brachial plexus avulsion injury; complex regional pain syndrome, drugtherapy induced neuralgia, cancer chemotherapy induced neuralgia,anti-retroviral therapy induced neuralgia; post spinal cord injury pain,small fiber neuropathy, idiopathic small-fiber neuropathy, idiopathicsensory neuropathy or trigeminal autonomic cephalalgia.

In another aspect, the invention features a compound of the invention,or a pharmaceutically acceptable salt or pharmaceutical compositionthereof, for use in a method of treating or lessening the severity in asubject of musculoskeletal pain. In some aspects, the musculoskeletalpain comprises osteoarthritis pain.

In another aspect, the invention features a compound of the invention,or a pharmaceutically acceptable salt or pharmaceutical compositionthereof, for use in a method of treating or lessening the severity in asubject of musculoskeletal pain, wherein musculoskeletal pain comprisesosteoarthritis pain, back pain, cold pain, burn pain or dental pain.

In another aspect, the invention features a compound of the invention,or a pharmaceutically acceptable salt or pharmaceutical compositionthereof, for use in a method of treating or lessening the severity in asubject of inflammatory pain, wherein inflammatory pain comprisesrheumatoid arthritis pain or vulvodynia.

In another aspect, the invention features a compound of the invention,or a pharmaceutically acceptable salt or pharmaceutical compositionthereof, for use in a method of treating or lessening the severity in asubject of inflammatory pain, wherein inflammatory pain comprisesrheumatoid arthritis pain.

In another aspect, the invention features a compound of the invention,or a pharmaceutically acceptable salt or pharmaceutical compositionthereof, for use in a method of treating or lessening the severity in asubject of idiopathic pain, wherein idiopathic pain comprisesfibromyalgia pain.

In another aspect, the invention features a compound of the invention,or a pharmaceutically acceptable salt or pharmaceutical compositionthereof, for use in a method of treating or lessening the severity in asubject of pathological cough.

In another aspect, the invention features a compound of the invention,or a pharmaceutically acceptable salt or pharmaceutical compositionthereof, for use in a method of treating or lessening the severity in asubject of acute pain. In some aspects, the acute pain comprises acutepost-operative pain.

In another aspect, the invention features a compound of the invention,or a pharmaceutically acceptable salt or pharmaceutical compositionthereof, for use in a method of treating or lessening the severity in asubject of postsurgical pain (e.g., herniorrhaphy pain, bunionectomypain or abdominoplasty pain).

In another aspect, the invention features a compound of the invention,or a pharmaceutically acceptable salt or pharmaceutical compositionthereof, for use in a method of treating or lessening the severity in asubject of bunionectomy pain.

In another aspect, the invention features a compound of the invention,or a pharmaceutically acceptable salt or pharmaceutical compositionthereof, for use in a method of treating or lessening the severity in asubject of heriorrhaphy pain.

In another aspect, the invention features a compound of the invention,or a pharmaceutically acceptable salt or pharmaceutical compositionthereof, for use in a method of treating or lessening the severity in asubject of abdominoplasty pain.

In another aspect, the invention features a compound of the invention,or a pharmaceutically acceptable salt or pharmaceutical compositionthereof, for use in a method of treating or lessening the severity in asubject of visceral pain. In some aspects, the visceral pain comprisesvisceral pain from abdominoplasty.

In another aspect, the invention features a compound of the invention,or a pharmaceutically acceptable salt or pharmaceutical compositionthereof, for use in a method wherein the subject is treated with one ormore additional therapeutic agents administered concurrently with, priorto, or subsequent to treatment with an effective amount of the compound,pharmaceutically acceptable salt or pharmaceutical composition. In someembodiments, the additional therapeutic agent is a sodium channelinhibitor.

In another aspect, the invention features a compound of the invention,or a pharmaceutically acceptable salt or pharmaceutical compositionthereof, for use in a method of inhibiting a voltage-gated sodiumchannel in a biological sample comprising contacting the biologicalsample with an effective amount of a compound of the invention, apharmaceutically acceptable salt thereof or a pharmaceutical compositionthereof. In another aspect, the voltage-gated sodium channel isNa_(V)1.8.

In another aspect, the invention features a compound of the invention,or a pharmaceutically acceptable salt or pharmaceutical compositionthereof, for use in a method of treating or lessening the severity in asubject of acute pain, chronic pain, neuropathic pain, inflammatorypain, arthritis, migraine, cluster headaches, trigeminal neuralgia,herpetic neuralgia, general neuralgias, epilepsy, epilepsy conditions,neurodegenerative disorders, psychiatric disorders, anxiety, depression,bipolar disorder, myotonia, arrhythmia, movement disorders,neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowelsyndrome, incontinence, pathological cough, visceral pain,osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy,radicular pain, sciatica, back pain, head pain, neck pain, severe pain,intractable pain, nociceptive pain, breakthrough pain, postsurgical pain(e.g., herniorrhaphy pain, bunionectomy pain or abdominoplasty pain),cancer pain, stroke, cerebral ischemia, traumatic brain injury,amyotrophic lateral sclerosis, stress induced angina, exercise inducedangina, palpitations, hypertension, or abnormal gastro-intestinalmotility.

In another aspect, the invention features a compound of the invention,or a pharmaceutically acceptable salt or pharmaceutical compositionthereof, for use in a method of treating or lessening the severity in asubject of femur cancer pain; non-malignant chronic bone pain;rheumatoid arthritis; osteoarthritis; spinal stenosis; neuropathic lowback pain; myofascial pain syndrome; fibromyalgia; temporomandibularjoint pain; chronic visceral pain, abdominal pain; pancreatic pain; IBSpain; chronic and acute headache pain; migraine; tension headache;cluster headaches; chronic and acute neuropathic pain, post-herpeticneuralgia; diabetic neuropathy; HIV-associated neuropathy; trigeminalneuralgia; Charcot-Marie-Tooth neuropathy; hereditary sensoryneuropathy; peripheral nerve injury; painful neuromas; ectopic proximaland distal discharges; radiculopathy; chemotherapy induced neuropathicpain; radiotherapy-induced neuropathic pain; post-mastectomy pain;central pain; spinal cord injury pain; post-stroke pain; thalamic pain;complex regional pain syndrome; phantom pain; intractable pain; acutepain, acute post-operative pain; acute musculoskeletal pain; joint pain;mechanical low back pain; neck pain; tendonitis; injury pain; exercisepain; acute visceral pain; pyelonephritis; appendicitis; cholecystitis;intestinal obstruction; hernias; chest pain, cardiac pain; pelvic pain,renal colic pain, acute obstetric pain, labor pain; cesarean sectionpain; acute inflammatory pain, burn pain, trauma pain; acuteintermittent pain, endometriosis; acute herpes zoster pain; sickle cellanemia; acute pancreatitis; breakthrough pain; orofacial pain; sinusitispain; dental pain; multiple sclerosis (MS) pain; pain in depression;leprosy pain; Behcet's disease pain; adiposis dolorosa; phlebitic pain;Guillain-Barre pain; painful legs and moving toes; Haglund syndrome;erythromelalgia pain; Fabry's disease pain; bladder and urogenitaldisease; urinary incontinence, pathological cough; hyperactive bladder;painful bladder syndrome; interstitial cystitis (IC); prostatitis;complex regional pain syndrome (CRPS), type I, complex regional painsyndrome (CRPS) type II; widespread pain, paroxysmal extreme pain,pruritus, tinnitus, or angina-induced pain.

Manufacture of Medicaments

In another aspect, the invention provides the use of a compound of theinvention, or a pharmaceutically acceptable salt or pharmaceuticalcomposition thereof, for the manufacture of a medicament.

In another aspect, the invention provides the use of a compound of theinvention, a pharmaceutically acceptable salt thereof, or apharmaceutical composition thereof for the manufacture of a medicamentfor use in inhibiting a voltage-gated sodium channel. In another aspect,the voltage-gated sodium channel is Na_(V)1.8.

In yet another aspect, the invention provides the use of a compound ofthe invention, a pharmaceutically acceptable salt thereof, or apharmaceutical composition thereof for the manufacture of a medicamentfor use in treating or lessening the severity in a subject of chronicpain, gut pain, neuropathic pain, musculoskeletal pain, acute pain,inflammatory pain, cancer pain, idiopathic pain, postsurgical pain(e.g., herniorrhaphy pain, bunionectomy pain or abdominoplasty pain),visceral pain, multiple sclerosis, Charcot-Marie-Tooth syndrome,incontinence, pathological cough, or cardiac arrhythmia.

In yet another aspect, the invention provides the use of a compound ofthe invention, a pharmaceutically acceptable salt thereof, or apharmaceutical composition thereof for the manufacture of a medicamentfor use in treating or lessening the severity in a subject of chronicpain, gut pain, neuropathic pain, musculoskeletal pain, acute pain,inflammatory pain, cancer pain, idiopathic pain, postsurgical pain,herniorrhaphy pain, bunionectomy pain, multiple sclerosis,Charcot-Marie-Tooth syndrome, incontinence, or cardiac arrhythmia.

In yet another aspect, the invention provides the use of the compound,pharmaceutically acceptable salt, or pharmaceutical compositiondescribed herein for the manufacture of a medicament for use in treatingor lessening the severity in a subject of gut pain, wherein gut paincomprises inflammatory bowel disease pain, Crohn's disease pain orinterstitial cystitis pain.

In yet another aspect, the invention provides a compound of theinvention, a pharmaceutically acceptable salt thereof, or apharmaceutical composition thereof for the manufacture of a medicamentfor use in treating or lessening the severity in a subject ofneuropathic pain. In some aspects, the neuropathic pain comprisespost-herpetic neuralgia, small fiber neuropathy or idiopathicsmall-fiber neuropathy.

In yet another aspect, the invention provides the use of a compound ofthe invention, a pharmaceutically acceptable salt thereof, or apharmaceutical composition thereof for the manufacture of a medicamentfor use in a treating or lessening the severity in a subject ofneuropathic pain, wherein neuropathic pain comprises post-herpeticneuralgia, diabetic neuralgia, painful HIV-associated sensoryneuropathy, trigeminal neuralgia, burning mouth syndrome,post-amputation pain, phantom pain, painful neuroma; traumatic neuroma;Morton's neuroma; nerve entrapment injury, spinal stenosis, carpaltunnel syndrome, radicular pain, sciatica pain; nerve avulsion injury,brachial plexus avulsion injury; complex regional pain syndrome, drugtherapy induced neuralgia, cancer chemotherapy induced neuralgia,anti-retroviral therapy induced neuralgia; post spinal cord injury pain,small fiber neuropathy, idiopathic small-fiber neuropathy, idiopathicsensory neuropathy or trigeminal autonomic neuropathy.

In yet another aspect, the invention provides the use of a compound ofthe invention, a pharmaceutically acceptable salt thereof, or apharmaceutical composition thereof for the manufacture of a medicamentfor use in treating or lessening the severity in a subject ofmusculoskeletal pain. In some aspects the musculoskeletal pain comprisesosteoarthritis pain.

In yet another aspect, the invention provides the use of a compound ofthe invention, a pharmaceutically acceptable salt thereof, or apharmaceutical composition thereof for the manufacture of a medicamentfor use in treating or lessening the severity in a subject ofmusculoskeletal pain, wherein musculoskeletal pain comprisesosteoarthritis pain, back pain, cold pain, burn pain or dental pain.

In yet another aspect, the invention provides the use of a compound ofthe invention, a pharmaceutically acceptable salt thereof, or apharmaceutical composition thereof for the manufacture of a medicamentfor use in treating or lessening the severity in a subject ofinflammatory pain, wherein inflammatory pain comprises rheumatoidarthritis pain or vulvodynia.

In yet another aspect, the invention provides the use of a compound ofthe invention, a pharmaceutically acceptable salt thereof, or apharmaceutical composition thereof for the manufacture of a medicamentfor use in treating or lessening the severity in a subject ofinflammatory pain, wherein inflammatory pain comprises rheumatoidarthritis pain.

In yet another aspect, the invention provides the use of a compound ofthe invention, a pharmaceutically acceptable salt thereof, or apharmaceutical composition thereof for the manufacture of a medicamentfor use in treating or lessening the severity in a subject of idiopathicpain, wherein idiopathic pain comprises fibromyalgia pain.

In yet another aspect, the invention provides the use of a compound ofthe invention, a pharmaceutically acceptable salt thereof, or apharmaceutical composition thereof for the manufacture of a medicamentfor use in treating or lessening the severity in a subject ofpathological cough.

In yet another aspect, the invention provides the use of a compound ofthe invention, a pharmaceutically acceptable salt thereof, or apharmaceutical composition thereof for the manufacture of a medicamentfor use in treating or lessening the severity in a subject of acutepain. In some aspects, the acute pain comprises acute post-operativepain.

In yet another aspect, the invention provides the use of a compound ofthe invention, a pharmaceutically acceptable salt thereof, or apharmaceutical composition thereof for the manufacture of a medicamentfor use in treating or lessening the severity in a subject ofpostsurgical pain (e.g., herniorrhaphy pain, bunionectomy pain orabdominoplasty pain).

In yet another aspect, the invention provides the use of a compound ofthe invention, a pharmaceutically acceptable salt thereof, or apharmaceutical composition thereof for the manufacture of a medicamentfor use in treating or lessening the severity in a subject ofherniorrhaphy pain.

In yet another aspect, the invention provides the use of a compound ofthe invention, a pharmaceutically acceptable salt thereof, or apharmaceutical composition thereof for the manufacture of a medicamentfor use in treating or lessening the severity in a subject ofbunionectomy pain.

In yet another aspect, the invention provides the use of a compound ofthe invention, a pharmaceutically acceptable salt thereof, or apharmaceutical composition thereof for the manufacture of a medicamentfor use in treating or lessening the severity in a subject ofabdominoplasty pain.

In yet another aspect, the invention provides the use of a compound ofthe invention, a pharmaceutically acceptable salt thereof, or apharmaceutical composition thereof for the manufacture of a medicamentfor use in treating or lessening the severity in a subject of visceralpain. In some aspects, the visceral pain comprises visceral pain fromabdominoplasty.

In yet another aspect, the invention provides the use of a compound ofthe invention, a pharmaceutically acceptable salt thereof, or apharmaceutical composition thereof for the manufacture of a medicamentfor use in combination with one or more additional therapeutic agentsadministered concurrently with, prior to, or subsequent to treatmentwith the compound or pharmaceutical composition. In some embodiments,the additional therapeutic agent is a sodium channel inhibitor.

In another aspect, the invention provides the use of a compound of theinvention, a pharmaceutically acceptable salt thereof, or apharmaceutical composition thereof for the manufacture of a medicamentfor use in treating or lessening the severity of acute pain, chronicpain, neuropathic pain, inflammatory pain, arthritis, migraine, clusterheadaches, trigeminal neuralgia, herpetic neuralgia, general neuralgias,epilepsy, epilepsy conditions, neurodegenerative disorders, psychiatricdisorders, anxiety, depression, bipolar disorder, myotonia, arrhythmia,movement disorders, neuroendocrine disorders, ataxia, multiplesclerosis, irritable bowel syndrome, incontinence, pathological cough,visceral pain, osteoarthritis pain, postherpetic neuralgia, diabeticneuropathy, radicular pain, sciatica, back pain, head pain, neck pain,severe pain, intractable pain, nociceptive pain, breakthrough pain,postsurgical pain (e.g., herniorrhaphy pain, bunionectomy pain orabdominoplasty pain), cancer pain, stroke, cerebral ischemia, traumaticbrain injury, amyotrophic lateral sclerosis, stress induced angina,exercise induced angina, palpitations, hypertension, or abnormalgastro-intestinal motility.

In another aspect, the invention provides the use of a compound of theinvention, a pharmaceutically acceptable salt thereof, or apharmaceutical composition thereof for the manufacture of a medicamentfor use in treating or lessening the severity of femur cancer pain;non-malignant chronic bone pain; rheumatoid arthritis; osteoarthritis;spinal stenosis; neuropathic low back pain; myofascial pain syndrome;fibromyalgia; temporomandibular joint pain; chronic visceral pain,abdominal pain; pancreatic pain; IBS pain; chronic and acute headachepain; migraine; tension headache; cluster headaches; chronic and acuteneuropathic pain, post-herpetic neuralgia; diabetic neuropathy;HIV-associated neuropathy; trigeminal neuralgia; Charcot-Marie-Toothneuropathy; hereditary sensory neuropathy; peripheral nerve injury;painful neuromas; ectopic proximal and distal discharges; radiculopathy;chemotherapy induced neuropathic pain; radiotherapy-induced neuropathicpain; post-mastectomy pain; central pain; spinal cord injury pain;post-stroke pain; thalamic pain; complex regional pain syndrome; phantompain; intractable pain; acute pain, acute post-operative pain; acutemusculoskeletal pain; joint pain; mechanical low back pain; neck pain;tendonitis; injury pain; exercise pain; acute visceral pain;pyelonephritis; appendicitis; cholecystitis; intestinal obstruction;hernias; chest pain, cardiac pain; pelvic pain, renal colic pain, acuteobstetric pain, labor pain; cesarean section pain; acute inflammatory,burn pain, trauma pain; acute intermittent pain, endometriosis; acuteherpes zoster pain; sickle cell anemia; acute pancreatitis; breakthroughpain; orofacial pain; sinusitis pain; dental pain; multiple sclerosis(MS) pain; pain in depression; leprosy pain; Behcet's disease pain;adiposis dolorosa; phlebitic pain; Guillain-Barre pain; painful legs andmoving toes; Haglund syndrome; erythromelalgia pain; Fabry's diseasepain; bladder and urogenital disease; urinary incontinence; pathologicalcough; hyperactive bladder; painful bladder syndrome; interstitialcystitis (IC); prostatitis; complex regional pain syndrome (CRPS) typeI; complex regional pain syndrome (CRPS) type II; widespread pain,paroxysmal extreme pain, pruritus, tinnitus, or angina-induced pain.

Administration of Pharmaceutically acceptable salts and compositions.

In certain embodiments of the invention an “effective amount” of acompound of the invention, a pharmaceutically acceptable salt thereof,or a pharmaceutical composition thereof is that amount effective fortreating or lessening the severity of one or more of the conditionsrecited above.

The compounds, salts, and compositions, according to the method of theinvention, may be administered using any amount and any route ofadministration effective for treating or lessening the severity of oneor more of the pain or non-pain diseases recited herein. The exactamount required will vary from subject to subject, depending on thespecies, age, and general condition of the subject, the severity of thecondition, the particular agent, its mode of administration, and thelike. The compounds, salts, and compositions of the invention arepreferably formulated in dosage unit form for ease of administration anduniformity of dosage. The expression “dosage unit form” as used hereinrefers to a physically discrete unit of agent appropriate for thesubject to be treated. It will be understood, however, that the totaldaily usage of the compounds, salts, and compositions of the inventionwill be decided by the attending physician within the scope of soundmedical judgment. The specific effective dose level for any particularsubject or organism will depend upon a variety of factors including thedisorder being treated and the severity of the disorder; the activity ofthe specific compound or salt employed; the specific compositionemployed; the age, body weight, general health, sex and diet of thesubject; the time of administration, route of administration, and rateof excretion of the specific compound or salt employed; the duration ofthe treatment; drugs used in combination or coincidental with thespecific compound or salt employed, and like factors well known in themedical arts. The term “subject” or “patient,” as used herein, means ananimal, preferably a mammal, and most preferably a human.

The pharmaceutically acceptable compositions of this invention can beadministered to humans and other animals orally, rectally, parenterally,intracisternally, intravaginally, intraperitoneally, topically (as bypowders, ointments, or drops), bucally, as an oral or nasal spray, orthe like, depending on the severity of the condition being treated. Incertain embodiments, the compound, salts, and compositions of theinvention may be administered orally or parenterally at dosage levels ofabout 0.001 mg/kg to about 100 mg/kg, or about 0.01 mg/kg to about 50mg/kg, of subject body weight per day, one or more times a day,effective to obtain the desired therapeutic effect.

Liquid dosage forms for oral administration include, but are not limitedto, pharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In addition to the active compound orsalt, the liquid dosage forms may contain inert diluents commonly usedin the art such as, for example, water or other solvents, solubilizingagents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butylene glycol, dimethylformamide, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor, and sesame oils),glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fattyacid esters of sorbitan, and mixtures thereof. Besides inert diluents,the oral compositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

In order to prolong the effect of the compounds of the invention, it isoften desirable to slow the absorption of the compounds fromsubcutaneous or intramuscular injection. This may be accomplished by theuse of a liquid suspension of crystalline or amorphous material withpoor water solubility. The rate of absorption of the compound thendepends upon its rate of dissolution that, in turn, may depend uponcrystal size and crystalline form. Alternatively, delayed absorption ofa parenterally administered compound form is accomplished by dissolvingor suspending the compound in an oil vehicle. Injectable depot forms aremade by forming microencapsule matrices of the compound in biodegradablepolymers such as polylactide-polyglycolide. Depending upon the ratio ofcompound to polymer and the nature of the particular polymer employed,the rate of compound release can be controlled. Examples of otherbiodegradable polymers include poly(orthoesters) and poly(anhydrides).Depot injectable formulations are also prepared by entrapping thecompound in liposomes or microemulsions that are compatible with bodytissues.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compound or salt ofthis invention with suitable non-irritating excipients or carriers suchas cocoa butter, polyethylene glycol or a suppository wax which aresolid at ambient temperature but liquid at body temperature andtherefore melt in the rectum or vaginal cavity and release the activecompound.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound or salt is mixed with at least one inert, pharmaceuticallyacceptable excipient or carrier such as sodium citrate or dicalciumphosphate and/or a) fillers or extenders such as starches, lactose,sucrose, glucose, mannitol, and silicic acid, b) binders such as, forexample, carboxymethylcellulose, alginates, gelatin,polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such asglycerol, d) disintegrating agents such as agar-agar, calcium carbonate,potato or tapioca starch, alginic acid, certain silicates, and sodiumcarbonate, e) solution retarding agents such as paraffin, f) absorptionaccelerators such as quaternary ammonium compounds, g) wetting agentssuch as, for example, cetyl alcohol and glycerol monostearate, h)absorbents such as kaolin and bentonite clay, and i) lubricants such astalc, calcium stearate, magnesium stearate, solid polyethylene glycols,sodium lauryl sulfate, and mixtures thereof. In the case of capsules,tablets and pills, the dosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like. The solid dosage forms of tablets, dragees, capsules, pills,and granules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes. Solid compositions of a similartype may also be employed as fillers in soft and hard-filled gelatincapsules using such excipients as lactose or milk sugar as well as highmolecular weight polyethylene glycols and the like.

The active compound or salt can also be in microencapsulated form withone or more excipients as noted above. The solid dosage forms oftablets, dragees, capsules, pills, and granules can be prepared withcoatings and shells such as enteric coatings, release controllingcoatings and other coatings well known in the pharmaceutical formulatingart. In such solid dosage forms the active compound or salt may beadmixed with at least one inert diluent such as sucrose, lactose orstarch. Such dosage forms may also comprise, as is normal practice,additional substances other than inert diluents, e.g., tabletinglubricants and other tableting aids such a magnesium stearate andmicrocrystalline cellulose. In the case of capsules, tablets and pills,the dosage forms may also comprise buffering agents. They may optionallycontain opacifying agents and can also be of a composition that theyrelease the active ingredient(s) only, or preferentially, in a certainpart of the intestinal tract, optionally, in a delayed manner. Examplesof embedding compositions that can be used include polymeric substancesand waxes.

Dosage forms for topical or transdermal administration of a compound orsalt of this invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, eardrops, and eye drops are also contemplated asbeing within the scope of this invention. Additionally, the inventioncontemplates the use of transdermal patches, which have the addedadvantage of providing controlled delivery of a compound to the body.Such dosage forms are prepared by dissolving or dispensing the compoundin the proper medium. Absorption enhancers can also be used to increasethe flux of the compound across the skin. The rate can be controlled byeither providing a rate controlling membrane or by dispersing thecompound in a polymer matrix or gel.

As described generally above, the compounds of the invention are usefulas inhibitors of voltage-gated sodium channels. In one embodiment, thecompounds are inhibitors of Na_(V)1.8 and thus, without wishing to bebound by any particular theory, the compounds, salts, and compositionsare particularly useful for treating or lessening the severity of adisease, condition, or disorder where activation or hyperactivity ofNa_(V)1.8 is implicated in the disease, condition, or disorder. Whenactivation or hyperactivity of Na_(V)1.8 is implicated in a particulardisease, condition, or disorder, the disease, condition, or disorder mayalso be referred to as a “Na_(V)1.8-mediated disease, condition ordisorder.” Accordingly, in another aspect, the invention provides amethod for treating or lessening the severity of a disease, condition,or disorder where activation or hyperactivity of Na_(V)1.8 is implicatedin the disease state.

The activity of a compound utilized in this invention as an inhibitor ofNa_(V)1.8 may be assayed according to methods described generally inInternational Publication No. WO 2014/120808 A9 and U.S. Publication No.2014/0213616 A1, both of which are incorporated by reference in theirentirety, methods described herein, and other methods known andavailable to one of ordinary skill in the art.

Additional Therapeutic Agents

It will also be appreciated that the compounds, salts, andpharmaceutically acceptable compositions of the invention can beemployed in combination therapies, that is, the compounds, salts, andpharmaceutically acceptable compositions can be administeredconcurrently with, prior to, or subsequent to, one or more other desiredtherapeutics or medical procedures. The particular combination oftherapies (therapeutics or procedures) to employ in a combinationregimen will take into account compatibility of the desired therapeuticsand/or procedures and the desired therapeutic effect to be achieved. Itwill also be appreciated that the therapies employed may achieve adesired effect for the same disorder (for example, an inventive compoundmay be administered concurrently with another agent used to treat thesame disorder), or they may achieve different effects (e.g., control ofany adverse effects). As used herein, additional therapeutic agents thatare normally administered to treat or prevent a particular disease, orcondition, are known as “appropriate for the disease, or condition,being treated.” For example, exemplary additional therapeutic agentsinclude, but are not limited to: non-opioid analgesics (indoles such asEtodolac, Indomethacin, Sulindac, Tolmetin; naphthylalkanones such asNabumetone; oxicams such as Piroxicam; para-aminophenol derivatives,such as Acetaminophen; propionic acids such as Fenoprofen, Flurbiprofen,Ibuprofen, Ketoprofen, Naproxen, Naproxen sodium, Oxaprozin; salicylatessuch as Aspirin, Choline magnesium trisalicylate, Diflunisal; fenamatessuch as meclofenamic acid, Mefenamic acid; and pyrazoles such asPhenylbutazone); or opioid (narcotic) agonists (such as Codeine,Fentanyl, Hydromorphone, Levorphanol, Meperidine, Methadone, Morphine,Oxycodone, Oxymorphone, Propoxyphene, Buprenorphine, Butorphanol,Dezocine, Nalbuphine, and Pentazocine). Additionally, nondrug analgesicapproaches may be utilized in conjunction with administration of one ormore compounds of the invention. For example, anesthesiologic(intraspinal infusion, neural blockade), neurosurgical (neurolysis ofCNS pathways), neurostimulatory (transcutaneous electrical nervestimulation, dorsal column stimulation), physiatric (physical therapy,orthotic devices, diathermy), or psychologic (cognitivemethods-hypnosis, biofeedback, or behavioral methods) approaches mayalso be utilized. Additional appropriate therapeutic agents orapproaches are described generally in The Merck Manual, NineteenthEdition, Ed. Robert S. Porter and Justin L. Kaplan, Merck Sharp & DohmeCorp., a subsidiary of Merck & Co., Inc., 2011, and the Food and DrugAdministration website, www.fda.gov, the entire contents of which arehereby incorporated by reference.

In another embodiment, additional appropriate therapeutic agents areselected from the following:

(1) an opioid analgesic, e.g. morphine, heroin, hydromorphone,oxymorphone, levorphanol, levallorphan, methadone, meperidine, fentanyl,cocaine, codeine, dihydrocodeine, oxycodone, hydrocodone, propoxyphene,nalmefene, nalorphine, naloxone, naltrexone, buprenorphine, butorphanol,nalbuphine, pentazocine, or difelikefalin;

(2) a nonsteroidal antiinflammatory drug (NSAID), e.g. aspirin,diclofenac, diflunisal, etodolac, fenbufen, fenoprofen, flufenisal,flurbiprofen, ibuprofen (including without limitation intravenousibuprofen (e.g., Caldolor®)), indomethacin, ketoprofen, ketorolac(including without limitation ketorolac tromethamine (e.g., Toradol®)),meclofenamic acid, mefenamic acid, meloxicam, nabumetone, naproxen,nimesulide, nitroflurbiprofen, olsalazine, oxaprozin, phenylbutazone,piroxicam, sulfasalazine, sulindac, tolmetin or zomepirac;

(3) a barbiturate sedative, e.g. amobarbital, aprobarbital,butabarbital, butalbital, mephobarbital, metharbital, methohexital,pentobarbital, phenobarbital, secobarbital, talbutal, thiamylal orthiopental;

(4) a benzodiazepine having a sedative action, e.g. chlordiazepoxide,clorazepate, diazepam, flurazepam, lorazepam, oxazepam, temazepam ortriazolam;

(5) a histamine (H₁) antagonist having a sedative action, e.g.diphenhydramine, pyrilamine, promethazine, chlorpheniramine orchlorcyclizine;

(6) a sedative such as glutethimide, meprobamate, methaqualone ordichloralphenazone;

(7) a skeletal muscle relaxant, e.g. baclofen, carisoprodol,chlorzoxazone, cyclobenzaprine, methocarbamol or orphenadrine;

(8) an NMDA receptor antagonist, e.g. dextromethorphan((+)-3-hydroxy-N-methylmorphinan) or its metabolite dextrorphan((+)-3-hydroxy-N-methylmorphinan), ketamine, memantine, pyrroloquinolinequinine, cis-4-(phosphonomethyl)-2-piperidinecarboxylic acid, budipine,EN-3231 (MorphiDex®), a combination formulation of morphine anddextromethorphan), topiramate, neramexane or perzinfotel including anNR2B antagonist, e.g. ifenprodil, traxoprodil or(−)-(R)-6-{2-[4-(3-fluorophenyl)-4-hydroxy-1-piperidinyl]-1-hydroxyethyl-3,4-dihydro-2(1H)-quinolinone;

(9) an alpha-adrenergic, e.g. doxazosin, tamsulosin, clonidine,guanfacine, dexmedetomidine, modafinil, or4-amino-6,7-dimethoxy-2-(5-methane-sulfonamido-1,2,3,4-tetrahydroisoquinolin-2-yl)-5-(2-pyridyl) quinazoline;

(10) a tricyclic antidepressant, e.g. desipramine, imipramine,amitriptyline or nortriptyline;

(11) an anticonvulsant, e.g. carbamazepine (Tegretol®), lamotrigine,topiramate, lacosamide (Vimpat®) or valproate;

(12) a tachykinin (NK) antagonist, particularly an NK-3, NK-2 or NK-1antagonist, e.g.(alphaR,9R)-7-[3,5-bis(trifluoromethyl)benzyl]-8,9,10,11-tetrahydro-9-methyl-5-(4-methylphenyl)-7H-[1,4]diazocino[2,1-g][1,7]-naphthyridine-6-13-dione(TAK-637),5-[[(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy-3-(4-fluorophenyl)-4-morpholinyl]-methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one(MK-869), aprepitant, lanepitant, dapitant or3-[[2-methoxy-5-(trifluoromethoxy)phenyl]-methylamino]-2-phenylpiperidine(2S,3S);

(13) a muscarinic antagonist, e.g oxybutynin, tolterodine, propiverine,tropsium chloride, darifenacin, solifenacin, temiverine and ipratropium;

(14) a COX-2 selective inhibitor, e.g. celecoxib, rofecoxib, parecoxib,valdecoxib, deracoxib, etoricoxib, or lumiracoxib;

(15) a coal-tar analgesic, in particular paracetamol;

(16) a neuroleptic such as droperidol, chlorpromazine, haloperidol,perphenazine, thioridazine, mesoridazine, trifluoperazine, fluphenazine,clozapine, olanzapine, risperidone, ziprasidone, quetiapine, sertindole,aripiprazole, sonepiprazole, blonanserin, iloperidone, perospirone,raclopride, zotepine, bifeprunox, asenapine, lurasidone, amisulpride,balaperidone, palindore, eplivanserin, osanetant, rimonabant,meclinertant, Miraxion® or sarizotan;

(17) a vanilloid receptor agonist (e.g. resinferatoxin or civamide) orantagonist (e.g. capsazepine, GRC-15300);

(18) a beta-adrenergic such as propranolol;

(19) a local anesthetic such as mexiletine;

(20) a corticosteroid such as dexamethasone;

(21) a 5-HT receptor agonist or antagonist, particularly a 5-HT_(1B/1D)agonist such as eletriptan, sumatriptan, naratriptan, zolmitriptan orrizatriptan;

(22) a 5-HT_(2A) receptor antagonist such asR(+)-alpha-(2,3-dimethoxy-phenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidinemethanol(MDL-100907);

(23) a cholinergic (nicotinic) analgesic, such as ispronicline(TC-1734), (E)-N-methyl-4-(3-pyridinyl)-3-buten-1-amine (RJR-2403),(R)-5-(2-azetidinylmethoxy)-2-chloropyridine (ABT-594) or nicotine;

(24) Tramadol®, Tramadol ER (Ultram ER®), Tapentadol ER (Nucynta®);

(25) a PDE5 inhibitor, such as5-[2-ethoxy-5-(4-methyl-1-piperazinyl-sulphonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one(sildenafil),(6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2′,1′:6,1]-pyrido[3,4-b]indole-1,4-dione(IC-351 or tadalafil),2-[2-ethoxy-5-(4-ethyl-piperazin-1-yl-1-sulphonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one(vardenafil),5-(5-acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,5-(5-acetyl-2-propoxy-3-pyridinyl)-3-ethyl-2-(1-isopropyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-[2-methoxyethyl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,4-[(3-chloro-4-methoxybenzyl)amino]-2-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-N-(pyrimidin-2-ylmethyl)pyrimidine-5-carboxamide,3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-4-propoxybenzenesulfonamide;

(26) an alpha-2-delta ligand such as gabapentin (Neurontin®), gabapentinGR (Gralise®), gabapentin, enacarbil (Horizant®), pregabalin (Lyrica®),3-methyl gabapentin,(1[alpha],3[alpha],5[alpha])(3-amino-methyl-bicyclo[3.2.0]hept-3-yl)-aceticacid, (3S,5R)-3-aminomethyl-5-methyl-heptanoic acid,(3S,5R)-3-amino-5-methyl-heptanoic acid,(3S,5R)-3-amino-5-methyl-octanoic acid,(2S,4S)-4-(3-chlorophenoxy)proline, (2S,4S)-4-(3-fluorobenzyl)-proline,[(1R,5R,6S)-6-(aminomethyl)bicyclo[3.2.0]hept-6-yl]acetic acid,3-(1-aminomethyl-cyclohexylmethyl)-4H-[1,2,4]oxadiazol-5-one,C-[1-(1H-tetrazol-5-ylmethyl)-cycloheptyl]-methylamine,(3S,4S)-(1-aminomethyl-3,4-dimethyl-cyclopentyl)-acetic acid,(3S,5R)-3-aminomethyl-5-methyl-octanoic acid,(3S,5R)-3-amino-5-methyl-nonanoic acid,(3S,5R)-3-amino-5-methyl-octanoic acid,(3R,4R,5R)-3-amino-4,5-dimethyl-heptanoic acid and(3R,4R,5R)-3-amino-4,5-dimethyl-octanoic acid;

(27) a cannabinoid such as KHK-6188;

(28) metabotropic glutamate subtype 1 receptor (mGluR1) antagonist;

(29) a serotonin reuptake inhibitor such as sertraline, sertralinemetabolite demethylsertraline, fluoxetine, norfluoxetine (fluoxetinedesmethyl metabolite), fluvoxamine, paroxetine, citalopram, citaloprammetabolite desmethylcitalopram, escitalopram, d,l-fenfluramine,femoxetine, ifoxetine, cyanodothiepin, litoxetine, dapoxetine,nefazodone, cericlamine and trazodone;

(30) a noradrenaline (norepinephrine) reuptake inhibitor, such asmaprotiline, lofepramine, mirtazepine, oxaprotiline, fezolamine,tomoxetine, mianserin, bupropion, bupropion metabolite hydroxybupropion,nomifensine and viloxazine (Vivalan®), especially a selectivenoradrenaline reuptake inhibitor such as reboxetine, in particular(S,S)-reboxetine;

(31) a dual serotonin-noradrenaline reuptake inhibitor, such asvenlafaxine, venlafaxine metabolite O-desmethylvenlafaxine,clomipramine, clomipramine metabolite desmethylclomipramine, duloxetine(Cymbalta®), milnacipran and imipramine;

(32) an inducible nitric oxide synthase (iNOS) inhibitor such asS-[2-[(1-iminoethyl)amino]ethyl]-L-homocysteine,S-[2-[(1-iminoethyl)-amino]ethyl]-4,4-dioxo-L-cysteine,S-[2-[(1-iminoethyl)amino]ethyl]-2-methyl-L-cysteine,(2S,5Z)-2-amino-2-methyl-7-[(1-iminoethyl)amino]-5-heptenoic acid,2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)-butyl]thio]-S-chloro-S-pyridinecarbonitrile;2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)butyl]thio]-4-chlorobenzonitrile,(2S,4R)-2-amino-4-[[2-chloro-5-(trifluoromethyl)phenyl]thio]-5-thiazolebutanol,2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)butyl]thio]-6-(trifluoromethyl)-3-pyridinecarbonitrile,2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)butyl]thio]-5-chlorobenzonitrile,N-[4-[2-(3-chlorobenzylamino)ethyl]phenyl]thiophene-2-carboxamidine,NXN-462, or guanidinoethyldisulfide;

(33) an acetylcholinesterase inhibitor such as donepezil;

(34) a prostaglandin E2 subtype 4 (EP4) antagonist such asN-[({2-[4-(2-ethyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethyl}amino)-carbonyl]-4-methylbenzenesulfonamideor4-[(15)-1-({[5-chloro-2-(3-fluorophenoxy)pyridin-3-yl]carbonyl}amino)ethyl]benzoicacid;

(35) a leukotriene B4 antagonist; such as1-(3-biphenyl-4-ylmethyl-4-hydroxy-chroman-7-yl)-cyclopentanecarboxylicacid (CP-105696),5-[2-(2-Carboxyethyl)-3-[6-(4-methoxyphenyl)-5E-hexenyl]oxyphenoxy]-valericacid (ONO-4057) or DPC-11870;

(36) a 5-lipoxygenase inhibitor, such as zileuton,6-[(3-fluoro-5-[4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl])phenoxy-methyl]-1-methyl-2-quinolone(ZD-2138), or 2,3,5-trimethyl-6-(3-pyridylmethyl)-1,4-benzoquinone(CV-6504);

(37) a sodium channel blocker, such as lidocaine, lidocaine plustetracaine cream (ZRS-201) or eslicarbazepine acetate;

(38) a Na_(V)1.7 blocker, such as XEN-402, XEN403, TV-45070,PF-05089771, CNV1014802, GDC-0276, RG7893 BIIB-074, BIIB-095, ASP-1807,DSP-3905, OLP-1002, RQ-00432979, FX-301, DWP-17061, IMB-110, IMB-111,IMB-112 and such as those disclosed in WO2011/140425 (US2011/306607);WO2012/106499 (US2012196869); WO2012/112743 (US2012245136);WO2012/125613 (US2012264749), WO2012/116440 (US2014187533), WO2011026240(US2012220605), U.S. Pat. Nos. 8,883,840, 8,466,188, or WO2013/109521(US2015005304), the entire contents of each application herebyincorporated by reference.

(38a) a Na_(V)1.7 blocker such as(2-benzylspiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-yl)-(4-isopropoxy-3-methyl-phenyl)methanone,2,2,2-trifluoro-1-[1′-[3-methoxy-4-[2-(trifluoromethoxy)ethoxy]benzoyl]-2,4-dimethyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-6-yl]ethanone,[8-fluoro-2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-yl]-(4-isobutoxy-3-methoxy-phenyl)methanone,1-(4-benzhydrylpiperazin-1-yl)-3-[2-(3,4-dimethylphenoxy)ethoxy]propan-2-ol,(4-butoxy-3-methoxy-phenyl)-[2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-yl]methanone,[8-fluoro-2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-yl]-(5-isopropoxy-6-methyl-2-pyridyl)methanone,(4-isopropoxy-3-methyl-phenyl)-[2-methyl-6-(1,1,2,2,2-pentafluoroethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-yl]methanone,5-[2-methyl-4-[2-methyl-6-(2,2,2-trifluoroacetyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-carbonyl]phenyl]pyridine-2-carbonitrile,(4-isopropoxy-3-methyl-phenyl)-[6-(trifluoromethyl)spiro[3,4-dihydro-2H-pyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-yl]methanone,2,2,2-trifluoro-1-[1′-[3-methoxy-4-[2-(trifluoromethoxy)ethoxy]benzoyl]-2-methyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-6-yl]ethanone,2,2,2-trifluoro-1-[1′-(5-isopropoxy-6-methyl-pyridine-2-carbonyl)-3,3-dimethyl-spiro[2,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-6-yl]ethanone,2,2,2-trifluoro-1-[1′-(5-isopentyloxypyridine-2-carbonyl)-2-methyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-6-yl]ethanone,(4-isopropoxy-3-methoxy-phenyl)-[2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-yl]methanone,2,2,2-trifluoro-1-[1′-(5-isopentyloxypyridine-2-carbonyl)-2,4-dimethyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-6-yl]ethanone,1-[(3S)-2,3-dimethyl-1′-[4-(3,3,3-trifluoropropoxymethyl)benzoyl]spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-6-yl]-2,2,2-trifluoro-ethanone,[8-fluoro-2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-yl]-[3-methoxy-4-[(1R)-1-methylpropoxy]phenyl]methanone,2,2,2-trifluoro-1-[1′-(5-isopropoxy-6-methyl-pyridine-2-carbonyl)-2,4-dimethyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-6-yl]ethanone,1-[1′-[4-methoxy-3-(trifluoromethyl)benzoyl]-2-methyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-6-yl]-2,2-dimethyl-propan-1-one,(4-isopropoxy-3-methyl-phenyl)-[2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-yl]methanone,[2-methyl-6-(1-methylcyclopropanecarbonyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-yl]-[4-(3,3,3-trifluoropropoxymethyl)phenyl]methanone,4-bromo-N-(4-bromophenyl)-3-[(1-methyl-2-oxo-4-piperidyl)sulfamoyl]benzamideor(3-chloro-4-isopropoxy-phenyl)-[2-methyl-6-(1,1,2,2,2-pentafluoroethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-yl]methanone.

(39) a Na_(V)1.8 blocker, such as PF-04531083, PF-06372865 and such asthose disclosed in WO2008/135826 (US2009048306), WO2006/011050(US2008312235), WO2013/061205 (US2014296313), US20130303535,WO2013131018, U.S. Pat. No. 8,466,188, WO2013114250 (US2013274243),WO2014/120808 (US2014213616), WO2014/120815 (US2014228371) WO2014/120820(US2014221435), WO2015/010065 (US20160152561), WO2015/089361(US20150166589) and WO2019014352 (US20190016671), the entire contents ofeach application hereby incorporated by reference.

(39a) a Na_(V)1.8 blocker such as4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide,2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(perfluoroethyl)benzamide,4,5-dichloro-2-(4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide,4,5-dichloro-2-(3-fluoro-4-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide,2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide,N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(4-(trifluoromethoxy)phenoxy)-4-(trifluoromethyl)benzamide,2-(4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(perfluoroethyl)benzamide,5-chloro-2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide,N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(4-(trifluoromethoxy)phenoxy)-5-(trifluoromethyl)benzamide,2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide,2-(2-chloro-4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide,5-chloro-2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide,4-chloro-2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide,5-chloro-2-(2-chloro-4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide,2-((5-fluoro-2-hydroxybenzyl)oxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide,N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(o-tolyloxy)-5-(trifluoromethyl)benzamide,2-(2,4-difluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide,N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(2-(trifluoromethoxy)phenoxy)-5-(trifluoromethyl)benzamide,2-(4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide,2-(4-fluoro-2-methyl-phenoxy)-N-(2-oxo-1H-pyridin-4-yl)-4-(trifluoromethyl)benzamide,[4-[[2-(4-fluoro-2-methyl-phenoxy)-4-(trifluoromethyl)benzoyl]amino]-2-oxo-1-pyridyl]methyldihydrogen phosphate,3-(4-fluoro-2-methoxyphenoxy)-N-(3-(methylsulfonyl)phenyl)quinoxaline-2-carboxamide,3-(2-chloro-4-fluorophenoxy)-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide,3-(2-chloro-4-methoxyphenoxy)-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide,3-(4-chloro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide,4-(3-(4-(trifluoromethoxy)phenoxy)quinoxaline-2-carboxamido)picolinicacid,2-(2,4-difluorophenoxy)-N-(3-sulfamoylphenyl)quinoline-3-carboxamide,2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)quinoline-3-carboxamide,3-(2,4-difluorophenoxy)-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide,N-(3-sulfamoylphenyl)-2-(4-(trifluoromethoxy)phenoxy)quinoline-3-carboxamide,N-(3-sulfamoylphenyl)-3-(4-(trifluoromethoxy)phenoxy)quinoxaline-2-carboxamide,3-(4-chloro-2-methylphenoxy)-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide,5-(3-(4-(trifluoromethoxy)phenoxy)quinoxaline-2-carboxamido)picolinicacid,3-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)quinoxaline-2-carboxamide,3-(4-fluoro-2-methoxyphenoxy)-N-(pyridin-4-yl)quinoxaline-2-carboxamide,3-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide,N-(3-cyanophenyl)-3-(4-fluoro-2-methoxyphenoxy)quinoxaline-2-carboxamide,N-(4-carbamoylphenyl)-3-(4-fluoro-2-methoxyphenoxy)quinoxaline-2-carboxamide,4-(3-(4-(trifluoromethoxy)phenoxy)quinoxaline-2-carboxamido)benzoicacid,N-(4-cyanophenyl)-3-(4-fluoro-2-methoxyphenoxy)quinoxaline-2-carboxamide,5-(4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)benzamido)picolinic acid,5-(2-(2,4-dimethoxyphenoxy)-4,6-bis(trifluoromethyl)benzamido)picolinicacid, 4-(4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)benzamido)benzoicacid,5-(2-(4-fluoro-2-methoxyphenoxy)-4,6-bis(trifluoromethyl)benzamido)picolinicacid,4-(2-(4-fluoro-2-methoxyphenoxy)-4-(perfluoroethyl)benzamido)benzoicacid,5-(2-(4-fluoro-2-methoxyphenoxy)-4-(perfluoroethyl)benzamido)picolinicacid,4-(2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)benzoicacid, 5-(4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)benzamido)picolinicacid,4-(2-(2-chloro-4-fluorophenoxy)-4-(perfluoroethyl)benzamido)benzoicacid,4-(2-(4-fluoro-2-methylphenoxy)-4-(perfluoroethyl)benzamido)benzoicacid, 4-(4,5-dichloro-2-(4-(trifluoromethoxy)phenoxy)benzamido)benzoicacid, 4-(4,5-dichloro-2-(4-chloro-2-methylphenoxy)benzamido)benzoicacid, 5-(4-(tert-butyl)-2-(4-fluoro-2-methoxyphenoxy)benzamido)picolinicacid, 5-(4,5-dichloro-2-(4-(trifluoromethoxy)phenoxy)benzamido)picolinicacid, 4-(4,5-dichloro-2-(4-fluoro-2-methylphenoxy)benzamido)benzoicacid, 5-(4,5-dichloro-2-(2,4-dimethoxyphenoxy)benzamido)picolinic acid,5-(4,5-dichloro-2-(2-chloro-4-fluorophenoxy)benzamido)picolinic acid,5-(4,5-dichloro-2-(4-fluoro-2-methylphenoxy)benzamido)picolinic acid,4-(4,5-dichloro-2-(4-chloro-2-methoxyphenoxy)benzamido)benzoic acid,5-(4,5-dichloro-2-(2,4-difluorophenoxy)benzamido)picolinic acid,2-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide,2-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide,2-(2-chloro-4-fluorophenoxy)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide,2-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide,2-(2-chloro-4-fluorophenoxy)-N-(3-sulfamoylphenyl)-6-(trifluoromethyl)benzamide,2-(2-chloro-4-fluorophenoxy)-5-(difluoromethyl)-N-(3-sulfamoylphenyl)benzamide,2-(4-fluorophenoxy)-4-(perfluoroethyl)-N-(3-sulfamoylphenyl)benzamide,2-(4-chloro-2-methoxyphenoxy)-4-(perfluoroethyl)-N-(3-sulfamoylphenyl)benzamide,2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide,5-chloro-2-(4-fluoro-2-methylphenoxy)-N-(3-sulfamoylphenyl)benzamide,4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)benzamide,2,4-dichloro-6-(4-chloro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)benzamide,2,4-dichloro-6-(4-fluoro-2-methylphenoxy)-N-(3-sulfamoylphenyl)benzamide,2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4,6-bis(trifluoromethyl)benzamide,2-(4-fluoro-2-methylphenoxy)-N-(3-sulfamoylphenyl)-4,6-bis(trifluoromethyl)benzamide,5-chloro-2-(2-chloro-4-fluorophenoxy)-N-(3-sulfamoylphenyl)benzamide,2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethoxy)benzamide,2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide,4,5-dichloro-2-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)benzamide,2-(4-fluoro-2-methoxyphenoxy)-4-(perfluoroethyl)-N-(3-sulfamoylphenyl)benzamide,5-fluoro-2-(4-fluoro-2-methylphenoxy)-N-(3-sulfamoylphenyl)benzamide,2-(2-chloro-4-fluorophenoxy)-4-cyano-N-(3-sulfamoylphenyl)benzamide,N-(3-sulfamoylphenyl)-2-(4-(trifluoromethoxy)phenoxy)-4-(trifluoromethyl)benzamide,N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide,N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide,N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethoxy)benzamide,4-[[2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide,4-[[3-chloro-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide,4-[[2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide,N-(3-carbamoyl-4-fluoro-phenyl)-3-(difluoromethyl)-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzamide,4-[[2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethoxy)benzoyl]amino]pyridine-2-carboxamide,N-(3-carbamoyl-4-fluoro-phenyl)-6-[2-chloro-4-(trifluoromethoxy)phenoxy]-2-fluoro-3-(trifluoromethyl)benzamide,N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[2-methyl-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide,N-(3-carbamoyl-4-fluoro-phenyl)-2,3,4-trifluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzamide,N-(2-carbamoyl-4-pyridyl)-3-fluoro-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine-4-carboxamide,4-[[6-[2-(difluoromethoxy)-4-(trifluoromethoxy)phenoxy]-2-fluoro-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide,N-(3-carbamoyl-4-fluoro-phenyl)-6-[3-chloro-4-(trifluoromethoxy)phenoxy]-2-fluoro-3-(trifluoromethyl)benzamide,N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide,N-(4-carbamoyl-3-fluoro-phenyl)-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide,4-[[2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide,N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[3-fluoro-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide,N-(3-carbamoyl-4-fluoro-phenyl)-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-5-(1,1,2,2,2-pentafluoroethyl)benzamide,4-[[4-(difluoromethoxy)-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide,N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[2-fluoro-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide,4-[[4-cyclopropyl-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide,N-(3-carbamoyl-4-fluoro-phenyl)-5-fluoro-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzamide,5-[[2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide,N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-(4-fluorophenoxy)-3-(trifluoromethyl)benzamide,or4-[[2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide.

(40) a combined Na_(V)1.7 and Na_(V)1.8 blocker, such as DSP-2230,Lohocla201 or BL-1021;

(41) a 5-HT3 antagonist, such as ondansetron;

(42) a TPRV 1 receptor agonist, such as capsaicin (NeurogesX®,Qutenza®); and the pharmaceutically acceptable salts and solvatesthereof,

(43) a nicotinic receptor antagonist, such as varenicline;

(44) an N-type calcium channel antagonist, such as Z-160;

(45) a nerve growth factor antagonist, such as tanezumab;

(46) an endopeptidase stimulant, such as senrebotase;

(47) an angiotensin II antagonist, such as EMA-401;

(48) acetaminophen (including without limitation intravenousacetaminophen (e.g., Ofirmev®));

(49) bupivacaine (including without limitation bupivacaine liposomeinjectable suspension (e.g., Exparel®) bupivacaine ER (Posimir),bupivacaine collagen (Xaracoll) and transdermal bupivacaine (Eladur®));and

(50) bupivacaine and meloxicam combination (e.g., HTX-011).

In one embodiment, the additional appropriate therapeutic agents areselected from V-116517, Pregabalin, controlled release Pregabalin,Ezogabine (Potiga®). Ketamine/amitriptyline topical cream (Amiket®),AVP-923, Perampanel (E-2007), Ralfinamide, transdermal bupivacaine(Eladur®), CNV1014802, JNJ-10234094 (Carisbamate), BMS-954561 orARC-4558.

In another embodiment, the additional appropriate therapeutic agents areselected fromN-(6-amino-5-(2,3,5-trichlorophenyl)pyridin-2-yl)acetamide;N-(6-amino-5-(2-chloro-5-methoxyphenyl)pyridin-2-yl)-1-methyl-1H-pyrazole-5-carboxamide;or3-((4-(4-(trifluoromethoxy)phenyl)-1H-imidazol-2-yl)methyl)oxetan-3-amine.

In another embodiment, the additional therapeutic agent is selected froma GlyT2/5HT2 inhibitor, such as Operanserin (VVZ149), a TRPV modulatorsuch as CA008, CMX-020, NE06860, FTABS, CNTX4975, MCP101, MDR16523, orMDR652, a EGRI inhibitor such as Brivoglide (AYX1), an NGF inhibitorsuch as Tanezumab, Fasinumab, ASP6294, MEDI7352, a Mu opioid agonistsuch as Cebranopadol, NKTR181 (oxycodegol), a CB-1 agonist such asNEO1940 (AZN1940), an imidazoline 12 agonist such as CR4056 or ap75NTR-Fc modulator such as LEVI-04.

In another embodiment, the additional therapeutic agent is oliceridineor ropivacaine (TLC590).

In another embodiment, the additional therapeutic agent is a sodiumchannel inhibitor (also known as a sodium channel blocker), such as theNa_(V)1.7 and Na_(V)1.8 blockers identified above.

The amount of additional therapeutic agent present in the compositionsof this invention may be no more than the amount that would normally beadministered in a composition comprising that therapeutic agent as theonly active agent. The amount of additional therapeutic agent in thepresently disclosed compositions may range from about 10% to 100% of theamount normally present in a composition comprising that agent as theonly therapeutically active agent.

The compounds and salts of this invention or pharmaceutically acceptablecompositions thereof may also be incorporated into compositions forcoating an implantable medical device, such as prostheses, artificialvalves, vascular grafts, stents and catheters. Accordingly, theinvention, in another aspect, includes a composition for coating animplantable device comprising a compound or salt of the invention asdescribed generally above, and in classes and subclasses herein, and acarrier suitable for coating said implantable device. In still anotheraspect, the invention includes an implantable device coated with acomposition comprising a compound or salt of the invention as describedgenerally above, and in classes and subclasses herein, and a carriersuitable for coating said implantable device. Suitable coatings and thegeneral preparation of coated implantable devices are described in U.S.Pat. Nos. 6,099,562; 5,886,026; and 5,304,121. The coatings aretypically biocompatible polymeric materials such as a hydrogel polymer,polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylacticacid, ethylene vinyl acetate, and mixtures thereof. The coatings mayoptionally be further covered by a suitable topcoat of fluorosilicone,polysaccharides, polyethylene glycol, phospholipids or combinationsthereof to impart controlled release characteristics in the composition.

Another aspect of the invention relates to inhibiting Na_(V)1.8 activityin a biological sample or a subject, which method comprisesadministering to the subject, or contacting said biological sample witha compound of the invention, a pharmaceutically acceptable salt thereof,or a pharmaceutical composition thereof. The term “biological sample,”as used herein, includes, without limitation, cell cultures or extractsthereof, biopsied material obtained from a mammal or extracts thereof,and blood, saliva, urine, feces, semen, tears, or other body fluids orextracts thereof.

Inhibition of Na_(V)1.8 activity in a biological sample is useful for avariety of purposes that are known to one of skill in the art. Examplesof such purposes include, but are not limited to, the study of sodiumchannels in biological and pathological phenomena; and the comparativeevaluation of new sodium channel inhibitors.

Synthesis of the Compounds of the Invention

The compounds of the invention can be prepared from known materials bythe methods described in the Examples, and other methods known to oneskilled in the art.

The compounds of the invention also can be prepared from known materialsby the following methods, similar methods, and other methods known toone skilled in the art. As one skilled in the art would appreciate, thefunctional groups of the intermediate compounds in the methods describedbelow may need to be protected by suitable protecting groups. Protectinggroups may be added or removed in accordance with standard techniques,which are well-known to those skilled in the art. The use of protectinggroups is described in detail in T. G. M. Wuts et al., Greene'sProtective Groups in Organic Synthesis (4th ed. 2006).

In general, the compounds of formulas (I) and (II) can be synthesizedaccording to the general methods outlined in Scheme 1 and the specificprocedures discussed in the Examples. Scheme 1 depicts the synthesis ofthe compounds of formula (I). The compounds of formula (II) can besynthesized by analogous methods. The starting materials for thesynthesis described in Scheme 1 and the Examples are commerciallyavailable or can be prepared according to methods known to one skilledin the art.

Radiolabeled Analogs of the Compounds of the Invention

In another aspect, the invention relates to radiolabeled analogs of thecompounds of the invention. As used herein, the term “radiolabeledanalogs of the compounds of the invention” refers to compounds that areidentical to the compounds of the invention, including the compounds offormulas (I) and (II), and all of the embodiments thereof, as describedherein, and the compounds identified in Tables A-D, as described herein,except that one or more atoms has been replaced with a radioisotope ofthe atom present in the compounds of the invention.

As used herein, the term “radioisotope” refers to an isotope of anelement that is known to undergo spontaneous radioactive decay. Examplesof radioisotopes include ³H, ⁴C, ³²P ³⁵S, ¹⁸F, ³⁶Cl, and the like, aswell as the isotopes for which no decay mode is identified in V. S.Shirley & C. M. Lederer, Isotopes Project, Nuclear Science Division,Lawrence Berkeley Laboratory, Table of Nuclides (January 1980).

The radiolabeled analogs can be used in a number of beneficial ways,including in various types of assays, such as substrate tissuedistribution assays. For example, tritium (3H)- and/or carbon-14(¹⁴C)-labeled compounds may be useful for various types of assays, suchas substrate tissue distribution assays, due to relatively simplepreparation and excellent detectability.

In another aspect, the invention relates to pharmaceutically acceptablesalts of the radiolabeled analogs, in accordance with any of theembodiments described herein in connection with the compounds of theinvention.

In another aspect, the invention relates to pharmaceutical compositionscomprising the radiolabeled analogs, or pharmaceutically acceptablesalts thereof, and a pharmaceutically acceptable carrier, adjuvant orvehicle, in accordance with any of the embodiments described herein inconnection with the compounds of the invention.

In another aspect, the invention relates to methods of inhibitingvoltage-gated sodium channels and methods of treating or lessening theseverity of various diseases and disorders, including pain, in a subjectcomprising administering an effective amount of the radiolabeledanalogs, pharmaceutically acceptable salts thereof, and pharmaceuticalcompositions thereof, in accordance with any of the embodimentsdescribed herein in connection with the compounds of the invention.

In another aspect, the invention relates to radiolabeled analogs,pharmaceutically acceptable salts thereof, and pharmaceuticalcompositions thereof, for use, in accordance with any of the embodimentsdescribed herein in connection with the compounds of the invention.

In another aspect, the invention relates to the use of the radiolabeledanalogs, or pharmaceutically acceptable salts thereof, andpharmaceutical compositions thereof, for the manufacture of medicaments,in accordance with any of the embodiments described herein in connectionwith the compounds of the invention.

In another aspect, the radiolabeled analogs, pharmaceutically acceptablesalts thereof, and pharmaceutical compositions thereof, can be employedin combination therapies, in accordance with any of the embodimentsdescribed herein in connection with the compounds of the invention.

EXAMPLES

General methods. ¹H NMR (400 MHz) spectra were obtained as solutions inan appropriate deuterated solvent such as dimethyl sulfoxide-d₆(DMSO-d6).

Compound purity, retention time, and electrospray mass spectrometry(ESI-MS) data were determined by LC/MS analysis using one of thefollowing methods or in another method described in the individualexamples.

LC/MS Method A. LC/MS analysis was conducted using a Waters AcquityUltra Performance LC system by reverse phase UPLC using an Acquity UPLCBEH C18 column (30×2.1 mm, 1.7 m particle) made by Waters (pn:186002349), and a dual gradient run from 1-99% mobile phase B over1.0-1.2 minutes. Mobile phase A=H₂O (0.05% CF₃CO₂H). Mobile phaseB═CH₃CN (0.035% CF₃CO₂H). Flow rate=1.5 mL/min, injection volume=1.5 μL,and column temperature=60° C.

LC/MS Method B. LC/MS analysis was conducted using a Waters AcquityUltra Performance LC system by reverse phase UPLC using an Acquity UPLCBEH C18 column (50×2.1 mm, 1.7 m particle) made by Waters (pn:186002350), and a dual gradient run from 1-99% mobile phase B over2.9-3.0 minutes. Mobile phase A=H₂O (0.05% CF₃CO₂H). Mobile phaseB═CH₃CN (0.035% CF₃CO₂H). Flow rate=1.2 mL/min, injection volume=1.5 μL,and column temperature=60° C.

LC/MS Method C. LC/MS analysis was conducted using a Waters AcquityUltra Performance LC system by reverse phase UPLC using an Acquity UPLCBEH C18 column (50×2.1 mm, 1.7 m particle) made by Waters (pn:186002350), and a dual gradient run from 1-99% mobile phase B over4.5-5.0 minutes. Mobile phase A=H₂O (0.05% CF₃CO₂H). Mobile phaseB═CH₃CN (0.035% CF₃CO₂H). Flow rate=1.2 mL/min, injection volume=1.5 μL,and column temperature=60° C.

LC/MS Method D. LC/MS analysis was conducted using an Acquity UPLC BEHC_(s) column (50×2.1 mm, 1.7 μm particle) made by Waters (pn: 186002877)with a (2.1×5 mm, 1.7 m particle) guard column (pn: 186003978), and adual gradient run from 2-98% mobile phase B over 1.15 minutes. Mobilephase A=H₂O (10 mM ammonium formate with 0.05% ammonium hydroxide).Mobile phase B=acetonitrile. Flow rate=1.0 mL/min, injection volume=2μL, and column temperature=45° C.

LC/MS Method E. LC/MS analysis was conducted using an Acquity UPLC BEHC₈ column (50×2.1 mm, 1.7 μm particle) made by Waters (pn: 186002877)with a (2.1×5 mm, 1.7 m particle) guard column (pn: 186003978), and adual gradient run from 2-98% mobile phase B over 4.45 minutes. Mobilephase A=H₂O (10 mM ammonium formate with 0.05% ammonium hydroxide).Mobile phase B=acetonitrile. Flow rate=0.6 mL/min, injection volume=2μL, and column temperature=45° C.

LC/MS Method F. LC/MS analysis was conducted using an Acquity UPLC BEHC₈ column (50×2.1 mm, 1.7 μm particle) made by Waters (pn: 186002877)with a (2.1×5 mm, 1.7 m particle) guard column (pn: 186003978), and adual gradient run from 2-98% mobile phase B over 1.5 minutes. Mobilephase A=H₂O (10 mM ammonium formate with 0.05% ammonium hydroxide).Mobile phase B=acetonitrile. Flow rate=0.6 mL/min, injection volume=2μL, and column temperature=45° C.

LC/MS Method G. LC/MS analysis was conducted using a Shimadzu 10-A LCsystem by reverse phase HPLC using an Onyx Monolithic C18 column (50×4.6mm) made by Phenomenex (pn:CHO-7644), and a dual gradient run from5-100% mobile phase B over 4.2 minutes. Mobile phase A ═H₂O (0.1%CF₃CO₂H). Mobile phase B═CH₃CN (0.1% CF₃CO₂H). Flow rate=1.5 mL/min,injection volume 10 μL and with the column at ambient temperature.

LC/MS Method H. LC/MS analysis was conducted using a Shimadzu 10-A LCsystem by reverse phase HPLC using an Onyx Monolithic C18 column (50×4.6mm) made by Phenomenex (pn:CHO-7644), and a dual gradient run from5-100% mobile phase B over 12 minutes. Mobile phase A ═H₂O (0.1%CF₃CO₂H). Mobile phase B═CH₃CN (0.1% CF₃CO₂H). Flow rate=1.5 mL/min,injection volume 10 μL and with the column at ambient temperature.

LC/MS Method I. LC/MS analysis was conducted using an Acquity UPLC HSST3 C_(s) column (50×2.1 mm, 1.8 μm particle) made by Waters (pn:186003538), and a dual gradient run from 1-99% mobile phase B over 2.90minutes. Mobile phase A=H₂O (10 mM ammonium formate). Mobile phaseB=acetonitrile. Flow rate=1.2 mL/min, injection volume=1.5 μL, andcolumn temperature=60° C.

LC/MS Method J. LC/MS analysis was conducted using Cortex 2.7 M C18 (3.0mm×50 mm) column made by Waters, at a temperature of 55° C. with a flowrate of 1.2 mL/minutes and a dual gradient run from 5-100% mobile phaseB over 4 minutes. Mobile phase A=water with 0.1% trifluoroacetic (TFA)acid. Mobile phase B=acetonitrile with 0.1% TFA acid.

LC/MS Method K. LC/MS analysis was conducted using a Phenomenex Luna C18column (3×50 mm, 3 m particle) over 2 minutes. Mobile phase conditions:5-95% acetonitrile (0.1% formic acid) with water (0.1% formic acid) over1 minute, then hold for 1 minute at 95% acetonitrile (0.1% formic acid).Flow rate=2 mL/min and column temperature 45° C.

LC/MS Method L: LC/MS analysis was conducted using a Phenomenex KinetexPolar C18 column (3×50 mm, 2.6 m particle) over 3 minutes. Mobile phaseconditions: 5-95% acetonitrile (0.1% formic acid) in water (0.1% formicacid). Flow rate=1.2 mL/min.

LC/MS Method M: LC/MS analysis was conducted using a Phenomenex KinetexPolar C18 column (3×50 mm, 2.6 m particle, Phenomenex) over 6 minutes.Mobile phase conditions: 5-95% acetonitrile (0.1% formic acid) in water(0.1% formic acid). Flow rate=1.2 mL/min.

LC/MS Method N: LC/MS analysis was conducted using a Millipore SigmaChromolith SpeedROD C18 column (50×4.6 mm, 2 m particle) over 12minutes. Mobile phase conditions: 5-100% acetonitrile (0.1%trifluoroacetic acid) in water (0.1% trifluoroacetic acid).

LC/MS Method O: LC/MS analysis was conducted using a Phenomenex Luna C18column (3×5 mm, 3 m particle) over 2.5 minutes. Mobile phase conditions:5-100% acetonitrile (0.1% formic acid) in water (0.1% formic acid) over1.3 minutes, then hold for 1.2 minutes at 95% acetonitrile (0.1% formicacid). Flow rate=1.5 mL/min and column temperature 45° C.

LC/MS Method P: LC/MS analysis was conducted using an Agilent ZORBAXExtend C18 column (4.6×50 mm 1.8 m particle) over 5 minutes. Mobilephase conditions: 10-90% acetonitrile in water (10 mM ammonium acetate).Flow rate=1.2 mL/min.

LCMS Method Q: LC/MS analysis was conducted using a Waters Cortecs C18column (3×50 mm, 2.7 m particle) over 6 minutes. Mobile phaseconditions: 5-100% acetonitrile (0.1% trifluoroacetic acid) in water(0.1% trifluoroacetic acid) over 4 minutes, then hold at 100%acetonitrile (0.1% trifluoroacetic acid) for 0.5 minutes, thenequilibration to 5% acetonitrile (0.1% trifluoroacetic acid) over 1.5minutes. Flow rate=1.2 mL/min and column temperature 55° C.

LC/MS Method R: LC/MS analysis was conducted using a YMC Triart C18column (2.1×33 mm. 3 m particle) over 3 minutes. Mobile phaseconditions: 2-98% acetonitrile in water (5 mM ammonium acetate). Flowrate=1.0 mL/min.

LC/MS Method S: LC/MS analysis was conducted using a Millipore SigmaChromolith SpeedROD C18 column (4.6×50 mm) over 6 minutes. Mobile phaseconditions: 5-95% acetonitrile (0.1% trifluoroacetic acid) in water(0.11% trifluoroacetic acid).

LC/MS Method T: LC/MS analysis was conducted using a Waters XBridge C18(4.6×50 mm, m particle) over 5 minutes. Mobile phase conditions 10-90%acetonitrile in water (10 mM ammonium acetate). Flow rate=1.2 mL/min.

LC/MS Method U: LC/MS analysis was conducted using a Waters Acquity BEHC18 column (2.1×50 mm, 1.7 m particle) over 4.5 minutes. Mobile phaseconditions 3-98% acetonitrile in water (0.1% formic acid). Flow rate=1.3mL/min and column temperature 35° C.

LC/MS Method V. LC/MS analysis was conducted using a MerckmilliporeChromolith SpeedROD C18 column (50×4.6 mm) and a dual gradient run from5-100% mobile phase B over 6 minutes. Mobile phase A=H₂O (0.1% TFA).Mobile phase B═CH₃CN (0.1% TFA).

LC/MS Method W. LC/MS analysis was conducted using a Waters Cortex C18column (50 mm×3.0 mm, 2.7 m particle). Mobile phase A=H₂O (0.1% TFA).Mobile phase B═CH₃CN (0.1% TFA), dual gradient from 5% to 100% mobilephase B over 4 minutes, 100% B for 0.5 minutes, with equilibration to 5%B over 1.5 min. Flow rate=1.2 mL/min and column temperature=55° C.

Unless otherwise noted, where purification by reverse phase HPLC isindicated in the Examples below, samples were purified using a reversephase HPLC-MS method using the general conditions as follows:

-   -   a. When using 5 mM HCl aqueous phase modifier: Phenomenex Luna        C18(2) column (30×75 mm, 5 μm particle size) using an        acetonitrile gradient runtime ranging from 9.5 minutes up to 15        minutes. Initial gradient acetonitrile concentration ranged from        1 to 40%, and final acetonitrile gradient concentration ranged        from 30 to 99%. Flow rate=50 mL/min, injection volume=950 μL,        and column temperature=25° C.    -   b. When using 0.1% ammonium hydroxide aqueous phase modifier:        Waters X-bridge OBD C18 column (19×150 mm, 5 μm particle size)        using an acetonitrile gradient run over 9 minutes. The        acetonitrile gradient concentration was either 38-53%        acetonitrile or 47-95% acetonitrile. Flow rate=19 mL/min.    -   c. When using 0.05% trifluoroacetic aqueous phase modifier:        Waters Sunfire C18 column (19×150 mm, 5 m particle size) with a        gradient from 1-100% acetonitrile over 11 minutes. Flow rate=19        mL/min.

Abbreviations

Unless otherwise noted, or where the context dictates otherwise, thefollowing abbreviations shall be understood to have the followingmeanings:

Abbreviation Meaning % w/v Weight-volume concentration[Ir(ppy)₂(dtbbpy)]PF₆[4,4′-Bis(1,1-dimethylethyl)-2,2′-bipyridine-N1,N1′]bis[2-(2-pyridinyl-N)phenyl-C] iridium (III) hexafluorophosphate 2-MeTHF2-methyltetrahydrofuran BSA Bovine Serum Albumin ca. Circa(approximately) CC2-DMPE Chlorocoumarin-2-dimyristoylphosphatidylethanolamine DCM Dichloromethane DCE Dichloroethane DIEA,DIPEA N, N-Diisopropyl ethyl amine DiSBAC₆(3)Bis-(1,3-dihexyl-thiobarbituric acid) trimethine oxonol DMAN,N-Dimethylacetamide DMAP 4-Dimethylaminopyridine DMEM Dulbecco'sModified Eagle's Medium DMF N,N-Dimethylformamide DMSO Dimethylsulfoxide DRG Dorsal root ganglia EDCI1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide ESI Electrosprayionization ESI-MS Electrospray mass spectrometry EtOAc Ethyl acetateEtOH Ethanol E-VIPR Electrical stimulation voltage ion probe reader FBSFetal bovine serum g Grams HATU1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxide hexafluorophosphate HEK Human embryonic kidney HEPES2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid HPLC Highperformance liquid chromatography HPLC/MS/MS High performance liquidchromatography/tandem mass spectrometry hr, h Hours HS Human serum HzHertz IS Internal standard KIR2.1 Inward-rectifier potassium ion channel2.1 L Liter(s) LC/MS Liquid chromatography-mass spectrometry LDA Lithiumdiisopropylamide M Molar (concentration) MeOH Methanol mg Milligrams MHzMegahertz min Minutes mL Milliliters mm Millimeters mM Millimolar(concentration) mmol Millimoles ms Millisecond MTBE Methyl tert-butylether N Normal (concentration) NBS N-Bromosuccinimide NEAA Non-essentialamino acids Ni(TMHD)₂ Nickel (II)bis(2,2,6,6-tetramethyl-3,5-heptanedionate) NIS N-Iodosuccinimide nLNanoliters nm Nanometer NMP N-Methylpyrrolidone NMR Nuclear magneticresonance Pd(dba)₂ Palladium (0) bis(dibenzylideneacetone) Pd(t-Bu₃P)₂Bis(tri-tert-butylphosphine) palladium (0) ppm Parts per million RBRound bottom (flask) RT Room temperature SFC Supercritical fluidchromatography T3P Propylphosphonic anhydride, i.e.,2,4,6-tripropyl-1,3,5,2,4,6- trioxatriphosphinane 2,4,6-trioxide TBSCltert-Butyldimethylchlorosilane t-BuOH tert-butyl alcohol tBuXPhos2-Di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl TEA TriethylamineTFA Trifluoroacetic acid THF Tetrahydrofuran UPLC Ultra performanceliquid chromatography VABSC-1 Voltage Assay Background SuppressionCompound μL Microliters μm Micrometers μM Micromolar (concentration)

Preparation 1 Methyl 4-amino-5-methyl-pyridine-2-carboxylate

2-Chloro-5-methyl-pyridin-4-amine (0.5 g, 4 mmol) was diluted inmethanol (6.6 mL) in an autoclave. Pd(dppf)Cl₂-dichloromethane (70 mg,0.086 mmol) and TEA (1.0 mL, 7.2 mmol) were added and the autoclave waspurged with nitrogen, then with carbon monoxide. The mixture was heatedto 130° C. and the carbon monoxide pressure was adjusted to 120 psi. Themixture was stirred for 18 hours at 130° C., and then cooled to 25° C.The mixture was purged with nitrogen and concentrated in vacuo. Afterpurification by silica gel chromatography (0-10% methanol/ethylacetate), the resulting material was triturated with MTBE (10 mL) for 1hour. The solid was isolated by filtration, washed with MTBE (5 mL) anddried under vacuum at 50° C. for 3 hours to provide methyl4-amino-5-methyl-pyridine-2-carboxylate (380 mg, 64%) as a beige solid.¹H NMR (400 MHz, CDCl₃) δ 8.20 (s, 1H), 7.39 (s, 1H), 4.31 (br s, 2H),3.95 (s, 3H), 2.16 (s, 3H) ppm. ESI-MS m z calc. 166.07, found 167.4(M+1)⁺; LC/MS retention time (Method K): 0.2 minutes.

Preparation 2 3-chloro-4-fluoro-2-methyl-phenol Step 1:(3-chloro-4-fluoro-phenyl) N,N-diethylcarbamate

A 500-mL round-bottom flask was charged with 3-chloro-4-fluorophenol(25.0 g, 165.5 mmol), N,N-diethylcarbamoyl chloride (45.1 g, 43.0 mL,326 mmol) and pyridine (125 mL). The resulting mixture was heated at100° C. and stirred at this temperature for 21 hours. The mixture wascooled to room temperature and was poured into water (250 mL). Theresulting solution was extracted with MTBE (2×125 mL). The combinedorganic layers were washed with 10% aqueous HCl (3×250 mL), 10% aqueousNaOH (2×250 mL), brine (125 mL), dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give (3-chloro-4-fluoro-phenyl)N,N-diethylcarbamate (41.2 g, 100%) as a yellow oil. ESI-MS m z calc.245.06, found 246.1 (M+1)⁺; LC/MS retention time (Method L): 2.06minutes. ¹H NMR (300 MHz, CDCl₃) δ 7.22 (dd, J=6.2, 2.6 Hz, 1H),7.17-7.07 (m, 1H), 7.06-6.97 (m, 1H), 3.48-3.33 (m, 4H), 1.32-1.15 (m,6H) ppm. ¹⁹F NMR (282 MHz, CDCl₃) δ −120.33-−120.55 (m, 1F) ppm.

Step 2: (3-chloro-4-fluoro-2-methyl-phenyl) N,N-diethylcarbamate

A 25-mL round-bottom flask under nitrogen was charged with(3-chloro-4-fluoro-phenyl) N,N-diethylcarbamate (500 mg, 1.97 mmol), THF(3 mL) and N,N,N,N-tetramethylethylenediamine (271 mg, 0.35 mL, 2.33mmol). The mixture was cooled to −78° C. and sec-butyllithium (1.7 mL of1.4 M solution in cyclohexane, 2.4 mmol) was then added slowly over ˜ 15minutes. The resulting mixture was stirred at −78° C. for 2 hours andthen treated with methyl iodide (480 mg, 0.21 mL, 3.4 mmol). Theresulting mixture was stirred for 2 hours while being allowed to warm to0° C. Water (5 mL) was then added and the resulting solution extractedwith MTBE (3×5 mL). The combined organic layers were washed with brine,dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo toprovide (3-chloro-4-fluoro-2-methyl-phenyl) N,N-diethylcarbamate (612mg, 104% yield, purity 87%) as a yellow oil. ESI-MS m z calc. 259.08,found 260.1 (M+1)⁺; LC/MS retention time (Method L): 2.11 minutes. ¹HNMR (300 MHz, CDCl₃) δ 7.05-6.93 (m, 2H), 3.47 (q, J=7.3 Hz, 2H), 3.39(q, J=7.1 Hz, 2H), 2.27 (s, 3H), 1.28 (t, J=7.2 Hz, 3H), 1.21 (t, J=7.2Hz, 3H) ppm. ¹⁹F NMR (282 MHz, CDCl₃) δ −116.99-17.13 (m, 1F) ppm.

Step 3: 3-chloro-4-fluoro-2-methyl-phenol

To a solution of (3-chloro-4-fluoro-2-methyl-phenyl)N,N-diethylcarbamate (508 mg, 1.96 mmol) in THF (3 mL) at roomtemperature was added LiAlH₄ (150 mg, 3.95 mmol) in one portion. Themixture was stirred at 50° C. for 6 hours and then at room temperature(˜15° C.) overnight. A saturated aqueous NH₄Cl solution (15 mL) wasadded dropwise to the mixture and the resulting suspension was stirredat room temperature for 20 minutes. The mixture was filtered over Celiteand the solid washed with MTBE (35 mL) and water (5 mL). The layers wereseparated and the aqueous layer was extracted with MTBE (2×35 mL). Thecombined organic layers were extracted with aqueous 2 M NaOH solution(4×20 mL). The combined aqueous layers were acidified (pH<4) withaqueous concentrated HCl (˜15 mL) and the resulting solution wasextracted with MTBE (3×50 mL). The combined organic layers were washedwith brine (25 mL), dried over Na₂SO₄ filtered and concentrated in vacuoto provide 3-chloro-4-fluoro-2-methyl-phenol (258 mg, 81%) as a lightbrown solid. ESI-MS m z calc. 160.01, found 159.1 (M−1)⁻; LC/MSretention time (Method L): 1.82 minutes. ¹H NMR (300 MHz, CDCl₃) δ 6.88(t, J=8.7 Hz, 1H), 6.65 (dd, J=8.8, 4.4 Hz, 1H), 4.70 (br. s., 1H), 2.32(s, 3H) ppm. ¹⁹F NMR (282 MHz, CDCl₃) δ −123.29 (d, J=12.2 Hz, 1F) ppm.

Preparation 3 2-chloro-3,4-difluoro-phenol Step 1:1,2-difluoro-4-(methoxymethoxy)benzene

To a mixture of 3,4-difluorophenol (10.0 g, 76.9 mmol) and K₂CO₃ (13.9g, 101 mmol) in acetone (100 mL) was added chloro(methoxy)methane (9.0g, 8.5 mL, 112 mmol). The resulting mixture was stirred for 2 days atroom temperature. Additional chloro(methoxy)methane (5.3 g, 5.0 mL, 66mmol) and diisopropylethylamine (9.6 g, 13 mL, 75 mmol) were added andthe mixture was stirred at 25° C. overnight. The mixture was filteredand the filtrate was concentrated in vacuo. The residue was purified bysilica gel chromatography (0-20% ethyl acetate/heptane) to provide1,2-difluoro-4-(methoxymethoxy)benzene (7.54 g, 56%) as a clear liquid.¹H NMR (300 MHz, CDCl₃) δ 7.06 (dt, J=10.0, 9.1 Hz, 1H), 6.89 (ddd,J=12.0, 6.8, 2.9 Hz, 1H), 6.74 (dtd, J=9.0, 3.3, 1.8 Hz, 1H), 5.11 (s,2H), 3.47 (s, 3H) ppm. ¹⁹F NMR (282 MHz, CDCl₃) δ −135.51 (dt, J=21.4,10.7 Hz, 1F), −146.74-−147.11 (m, 1F) ppm.

Step 2: 3-chloro-1,2-difluoro-4-(methoxymethoxy)benzene

2,2,6,6-Tetramethylpiperidine (5.27 g, 6.3 mL, 37 mmol) and1,2-difluoro-4-(methoxymethoxy)benzene (6.5 g, 37 mmol) were addedconsecutively to a solution of n-butyllithium (15 mL of 2.5 M inhexanes, 38 mmol) in THF (65 mL) at −78° C. After stirring for 2 hoursat −78° C., 1,1,2-trichloro-1,2,2-trifluoroethane (7.1 g, 4.5 mL, 38mmol) was added and the mixture was stirred at 0° C. for 1 hour. Water(100 mL) was added and the mixture was extracted with dichloromethane(3×100 mL). The combined organic layers were dried over Na₂SO₄, filteredand concentrated in vacuo. The residue was purified by silica gelchromatography (0-10% ethyl acetate/heptane) to provide3-chloro-1,2-difluoro-4-(methoxymethoxy)benzene (9.43 g, 85%) as yellowoil. ¹H NMR (300 MHz, CDCl₃) δ 7.02 (td, J=9.4, 8.2 Hz, 1H), 6.96-6.88(m, 1H), 5.21 (s, 2H), 3.52 (s, 3H) ppm. ¹⁹F NMR (282 MHz, CDCl₃) δ−135.20 (dd, J=21.4, 9.2 Hz, 1F), −143.05-−143.37 (m, 1F) ppm.

Step 3: 2-chloro-3,4-difluoro-phenol

Aqueous HCl (50 mL of 6 M, 300 mmol) was added to a solution of3-chloro-1,2-difluoro-4-(methoxymethoxy)benzene (9.43 g, 31.7 mmol) inTHF (55 mL) and the mixture was stirred at 25° C. overnight. The mixturewas diluted with water (100 mL) and extracted with diethyl ether (3×100mL). The combined organic layers were washed with brine (50 mL), driedover Na₂SO₄, filtered and concentrated in vacuo. The residue waspurified by silica gel chromatography (0-30% dichloromethane/pentane) toafford 2-chloro-3,4-difluoro-phenol (4.65 g, 66%) as yellow oil. ESI-MSm z calc. 163.984, found 163.0 (M−1)⁻; LC/MS retention time (Method M):2.34 minutes. ¹H NMR (300 MHz, CDCl₃) δ 7.02 (td, J=9.5, 8.5 Hz, 1H),6.76 (ddd, J=9.3, 4.2, 2.3 Hz, 1H), 5.50 (s, 1H) ppm. ¹⁹F NMR (282 MHz,CDCl₃) δ −136.22 (dd, J=21.4, 9.2 Hz, 1F), −144.97-−145.28 (m, 1F) ppm.

Preparation 4 2-cyclopropyl-3,6-difluoro-phenol Step 1:2-bromo-3,6-difluoro-phenol

To a solution of 2-bromo-1,4-difluoro-3-methoxy-benzene (1.0 g, 4.5mmol) in dichloromethane (5.0 mL) was added BBr₃ (4.5 g, 1.7 mL, 18mmol) dropwise at 0° C. The mixture was stirred for 2 hours at roomtemperature. Water was then added dropwise at 0° C. and the layersseparated. The organic layer was dried over anhydrous MgSO₄, filteredand concentrated in vacuo to provide 2-bromo-3,6-difluoro-phenol (1.04g, 100%) as colorless oil. LC/MS retention time=3.94 minutes (Method N).

Step 2: 2-cyclopropyl-3,6-difluoro-phenol

Nitrogen was bubbled though a solution of 2-bromo-3,6-difluoro-phenol(14.27 g, 68.28 mmol), cyclopropyl boronic acid (11.73 g, 136.6 mmol),K₃PO₄ (58.0 g, 273 mmol), tricyclohexylphosphonium tetrafluoroborate(2.51 g, 6.84 mmol) and Pd(OAc)₂ (3.07 g, 13.7 mmol) in a mixture oftoluene (265 mL) and water (65 mL) for 10 minutes in a pressure flask.The flask was sealed and heated at 100° C. overnight. After cooling, themixture was diluted with ethyl acetate (700 mL), washed with water andbrine, dried over MgSO₄ and filtered. The filtrate was concentrated invacuo and purified using silica gel chromatography (0-40% ethylacetate/hexane). The isolated product was dissolved in ethyl acetate(300 mL) and extracted with 1 M aqueous NaOH (4×50 mL). The combinedaqueous layers were adjusted to pH˜2 with 6 M aqueous HCl and extractedwith ethyl acetate (2×150 mL). The combined organic layers were washedwith water and brine, dried over MgSO₄ and filtered. The filtrate wasconcentrated in vacuo to obtain 2-cyclopropyl-3,6-difluoro-phenol (9.1g, 74%) as yellow oil. ESI-MS m z calc. 170.05, found 171.2 (M+1)⁺;LC/MS retention time (Method N): 4.86 minutes. ¹H NMR (500 MHz, CDCl₃) δ6.93-6.84 (m, 1H), 6.56-6.48 (m, 1H), 5.51 (d, J=4.0 Hz, 1H), 1.84-1.75(m, 1H), 1.05-0.97 (m, 2H), 0.97-0.89 (m, 2H) ppm.

Preparation 5 4-(difluoromethyl)-2-methoxy-phenol

(Diethylamino)sulfur trifluoride (39 g, 32 mL, 242 mmol) was slowlyadded to a cold (10° C.) solution of 4-hydroxy-3-methoxy-benzaldehyde(18.0 g, 118 mmol) in dichloromethane (300 mL). The mixture was warmedto room temperature and stirred overnight. The mixture was treated with5% aqueous NaHCO₃ (500 mL), stirred for 30 minutes, then extracted withdichloromethane (3×200 mL). The combined organic layers were dried overNa₂SO₄, filtered and concentrated in vacuo. The residue was purified bysilica gel chromatography (0-30% ethyl acetate/heptane) to afford4-(difluoromethyl)-2-methoxy-phenol (10.88 g, 47%) as an orange oil thatcrystallized on standing. ESI-MS m z calc. 174.0492, found 173.0 (M−1)⁻;LC/MS retention time (Method M): 2.03 minutes. ¹H NMR (300 MHz, CDCl₃) δ7.05-6.92 (m, 3H), 6.57 (t, J=61.1 Hz, 1H), 5.79 (s, 1H), 3.94 (s, 3H)ppm. ¹⁹F NMR (282 MHz, CDCl₃) δ −107.50-−107.92 (m, 2F) ppm.

Preparation 6 2,3-dichloro-4-fluoro-phenol Step 1:(3-chloro-4-fluoro-phenyl) N,N-diethylcarbamate

A 500-mL round-bottom flask was charged with 3-chloro-4-fluorophenol(25.0 g, 165.5 mmol), N,N-diethylcarbamoyl chloride (45 g, 43 mL, 326mmol) and pyridine (125 mL). The mixture was stirred at 100° C. for 21hours. The mixture was cooled to room temperature, poured into water(250 mL) and extracted with MTBE (2×125 mL). The combined organic layerswere washed with 10% aqueous HCl (3×250 mL), 10% aqueous NaOH (2×250 mL)and brine (125 mL). The organic layer was dried over Na₂SO₄, filteredand concentrated in vacuo to provide (3-chloro-4-fluoro-phenyl)N,N-diethylcarbamate (41.2 g, 100%) as a yellow oil (99% purity). ESI-MSm z calc. 245.06, found 246.1 (M+1)⁺; LC/MS retention time (Method L):2.06 minutes. ¹H NMR (300 MHz, CDCl₃) δ 7.22 (dd, J=6.2, 2.6 Hz, 1H),7.17-7.07 (m, 1H), 7.06-6.97 (m, 1H), 3.48-3.33 (m, 4H), 1.32-1.15 (m,6H) ppm. ¹⁹F NMR (282 MHz, CDCl₃) δ −120.33-−120.55 (m, 1F) ppm.

Step 2: (2,3-dichloro-4-fluoro-phenyl) N,N-diethylcarbamate

A flask under nitrogen was charged with (3-chloro-4-fluoro-phenyl)N,N-diethylcarbamate (10 g, 41 mmol), THF (60 mL) andN,N,N,N-tetramethylethylenediamine (5.4 g, 7.0 mL, 47 mmol). The mixturewas cooled to −78° C. and sec-butyllithium (34 mL of 1.4 M incyclohexane, 48 mmol) was then added slowly (over −15 min). The mixturewas stirred at −78° C. for 2 hours and then treated with1,1,2-trichloro-1,2,2-trifluoro-ethane (8.4 g, 5.3 mL, 45 mmol). Theresulting mixture was allowed to warm to 0° C. over 1 hour. Water (50mL) was then added and the resulting solution extracted with diethylether (3×150 mL). The combined organic layers were washed with brine (50mL), dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo.The residue was purified by silica gel chromatography (0-10% ethylacetate/heptane) to provide (2,3-dichloro-4-fluoro-phenyl)N,N-diethylcarbamate (8.92 g, 78%) as yellow oil. ESI-MS m z calc.279.02, found 280.1 (M+1)⁺; LC/MS retention time (Method L): 2.13minutes. ¹H NMR (300 MHz, CDCl₃) δ 7.23-6.92 (m, 2H), 3.55-3.30 (m, 4H),1.37-1.13 (m, 6H) ppm. ¹⁹F NMR (282 MHz, CDCl₃) δ −113.45 (d, J=6.1 Hz,1F) ppm.

Step 3: 2,3-dichloro-4-fluoro-phenol

LiAlH₄ (45 mg, 1.3 mmol) was added to a solution of(2,3-dichloro-4-fluoro-phenyl) N,N-diethylcarbamate (300 mg, 1.07 mmol)in THF (5 mL) and the mixture was stirred at room temperature overnight.Additional LiAlH₄ (40 mg, 1.2 mmol) was added and the mixture was heatedat 50° C. for 7 hours, and then at reflux for 2 hours. The mixture wascooled to room temperature, then treated slowly with a saturated aqueousNH₄Cl solution (50 mL) and stirred at room temperature for 20 minutes.The mixture was filtered over Celite and the solid washed with MTBE (50mL) and water (10 mL). The filtrate layers were separated and theaqueous layer was extracted with MTBE (2×50 mL). The combined organiclayers were then extracted with 2 M aqueous NaOH (4×25 mL). The combinedaqueous extracts were acidified (pH<4) with 6 M aqueous HCl and theresulting solution was extracted with diethyl ether (3×50 mL). Thecombined organic layers were washed with brine (10 mL), dried overNa₂SO₄, filtered and concentrated in vacuo. Silica gel chromatography(0-30% dichloromethane/pentane) provided 2,3-dichloro-4-fluoro-phenol(164 mg, 55%) as a yellow oil that solidified to an off-white solid uponstanding. ¹H NMR (300 MHz, CDCl₃) δ 7.02-6.91 (m, 1H), 6.90-6.81 (m, 1H)ppm. ¹⁹F NMR (282 MHz, CDCl₃) δ −120.56 (t, J=7.6 Hz, 1F) ppm.

Preparation 7 4-(difluoromethoxy)-3-fluoro-2-methoxy-phenol Step 1:1-bromo-4-(difluoromethoxy)-3-fluoro-2-methoxybenzene

A mixture of 4-bromo-2-fluoro-3-methoxy-phenol (11.5 g, 52.0 mmol),K₂CO₃ (28.8 g, 208 mmol) and sodium 2-chloro-2,2-difluoro-acetate (23.8g, 156 mmol) in DMF (200 mL) and water (50 mL) was degassed withnitrogen for 5 minutes and was heated at 100° C. for 18 hours. Themixture was cooled to room temperature, then extracted with diethylether (4×200 mL). The combined organic layers were washed with water(2×100 mL) and 1 M aqueous NaOH (2×100 mL). The organic phase was driedover anhydrous Na₂SO₄, filtered and concentrated in vacuo to provide1-bromo-4-(difluoromethoxy)-3-fluoro-2-methoxy-benzene (9.62 g, 64%) asa yellow oil. ¹H NMR (300 MHz, CDCl₃): δ 7.33-7.26 (m, 1H), 6.92-6.84(m, 1H), 6.53 (t, J=72.6 Hz, 1H), 3.99 (d, J=1.4 Hz, 3H) ppm. ¹⁹F NMR(282 MHz, CDCl₃): δ −81.8 (dd J=72.4 Hz, 4.3 Hz, 2F), −143.1 (s, 1F)ppm.

Step 2: 4-(difluoromethoxy)-3-fluoro-2-methoxy-phenol

A mixture of 1-bromo-4-(difluoromethoxy)-3-fluoro-2-methoxy-benzene (9.1g, 33.6 mmol), Me₄tButylXphos (493 mg, 1.03 mmol) and KOH (5.75 g, 102.5mmol) in dioxane (28 mL) and water (28 mL) was degassed with nitrogenbubbling for 10 minutes. Pd₂dba₃ (474 mg, 0.518 mmol) was added and thereaction vessel purged with nitrogen (3×). The mixture was stirred at90° C. for 3 hours, and then cooled to room temperature and diluted withwater (100 mL). The aqueous mixture was washed with ether (4×200 mL).The aqueous phase was then acidified with 3 M aqueous HCl until pH 1-2and extracted with ether (3×150 mL). The combined organic extracts werewashed with saturated aqueous NaHCO₃ (3×50 mL) and brine (50 mL), driedover Na₂SO₄, filtered and concentrated in vacuo to provide4-(difluoromethoxy)-3-fluoro-2-methoxy-phenol (5.90 g, 75%) as a lightorange oil. ESI-MS m z calc. 208.03, found 207.0 (M−1)⁻; LC/MS retentiontime (Method M): 2.33 minutes. ¹H NMR (300 MHz, CDCl₃) δ 6.90-6.79 (m,1H), 6.73-6.18 (m, 2H), 5.73-5.65 (m, 1H), 4.03 (d, J=2.1 Hz, 3H) ppm.¹⁹F NMR (282 MHz, CDCl₃) δ −81.05-−82.50 (m, 1F), −145.68-−146.31 (m,1F) ppm.

Preparation 8 2-ethyl-3-fluoro-4-(trifluoromethoxy)phenol Step 1:2-fluoro-4-(methoxymethoxy)-1-(trifluoromethoxy)benzene

To a solution of 3-fluoro-4-(trifluoromethoxy)phenol (5.0 g, 25.5 mmol)and DIPEA (9.6 g, 13 mL, 75 mmol) in dichloromethane (130 mL) at 0° C.was added chloromethyl methyl ether (3.7 g, 3.9 mL, 42 mmol). Theresulting mixture was stirred overnight at room temperature. The solventwas removed in vacuo and the residue purified by silica gelchromatography (0-40% dichloromethane/hexanes) to provide2-fluoro-4-(methoxymethoxy)-1-(trifluoromethoxy)benzene (5.11 g, 83%) asa colorless oil. ¹H NMR (300 MHz, CDCl₃) δ 7.20 (td, J=8.9, 1.0 Hz, 1H),6.91 (dd, J=11.6, 2.8 Hz, 1H), 6.81 (ddd, J=9.0, 2.9, 1.6 Hz, 1H), 5.15(s, 2H), 3.48 (s, 3H) ppm. ¹⁹F NMR (282 MHz, CDCl₃) δ −59.34 (br. s.,3F), −125.89-−126.37 (m, 1F) ppm.

Step 2: 2-ethyl-3-fluoro-1-(methoxymethoxy)-4-(trifluoromethoxy)benzene

To a solution of 2-fluoro-4-(methoxymethoxy)-1-(trifluoromethoxy)benzene(5.0 g, 20.8 mmol) in THF (100 mL) at −78° C. was added n-butyllithium(10 mL of 2.5 M in hexanes, 25 mmol) dropwise over 20 minutes. After 30minutes at this temperature, iodoethane (8.7 g, 4.5 mL, 56 mmol) wasadded dropwise over 10 minutes and the mixture was stirred at thistemperature for 30 minutes. The mixture was allowed to warm to 0° C. andstirred for 2 hours, and then stirred at ˜ 5° C. for 1.5 hours. Themixture was treated with saturated aqueous NaHCO₃ (75 mL) and water (50mL) and concentrated in vacuo to remove the organic solvents. Theremaining aqueous mixture was partitioned between water (100 mL) anddichloromethane (300 mL) and the layers separated. The aqueous layer wasextracted with additional dichloromethane. The combined organic layerswere dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo.Reverse phase chromatography (5-95% acetonitrile/0.1% aqueous formicacid) product fractions were combined and concentrated in vacuo toremove the acetonitrile. Water (200 mL) was added to the remainingaqueous mixture which was extracted with dichloromethane (3×). Thecombined organic layers were dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo to provide2-ethyl-3-fluoro-1-(methoxymethoxy)-4-(trifluoromethoxy)benzene (4.08 g,73%) as a pale yellow oil. ¹H NMR (300 MHz, CDCl₃) δ 7.11-6.99 (m, 1H),6.84 (d, J=9.1 Hz, 1H), 5.20 (s, 2H), 3.48 (s, 3H), 2.78-2.64 (m, 2H),1.16 (t, J=7.5 Hz, 3H) ppm. ¹⁹F NMR (282 MHz, CDCl₃) δ −59.20 (s, 3F),−132.77 (s, 1F) ppm.

Step 3: 2-ethyl-3-fluoro-4-(trifluoromethoxy)phenol

To a solution of2-ethyl-3-fluoro-1-(methoxymethoxy)-4-(trifluoromethoxy)benzene (4.08 g,15.2 mmol) in dioxane (60 mL) at room temperature was added aqueousconcentrated HCl (1.3 mL of 12 M, 15.6 mmol). The mixture was stirred at40° C. for 5 hours, and then overnight at 35° C. The mixture wasconcentrated in vacuo and partitioned between water (300 mL) anddichloromethane (150 mL). The layers were separated and the aqueouslayer was extracted with additional dichloromethane (100 mL). Thecombined organic extracts were dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. Reverse phase purification (5-95%acetonitrile/0.1% aqueous formic acid) provided product fractions whichwere combined and concentrated in vacuo to remove the acetonitrile.Water (200 mL) was added to the remaining aqueous mixture, which wasextracted with dichloromethane (3×). The combined organic layers weredried over anhydrous Na₂SO₄, filtered and concentrated in vacuo toprovide 2-ethyl-3-fluoro-4-(trifluoromethoxy)phenol (2.62 g, 76%) as ayellow oil. ¹H NMR (300 MHz, CDCl₃) δ 7.05-6.94 (m, 1H), 6.53 (dd,J=9.0, 1.9 Hz, 1H), 4.89 (d, J=1.2 Hz, 1H), 2.69 (qd, J=7.6, 1.9 Hz,2H), 1.19 (t, J=7.5 Hz, 3H) ppm. ¹⁹F NMR (282 MHz, CDCl₃) δ −59.32 (s,3F), −132.31-−132.53 (m, 1F) ppm.

Preparation 9 2-cyclopropyl-3-fluoro-4-(trifluoromethoxy)phenol Step 1:2-bromo-3-fluoro-1-(methoxymethoxy)-4-(trifluoromethoxy)benzene

To a solution of 2-fluoro-4-(methoxymethoxy)-1-(trifluoromethoxy)benzene(5.0 g, 20.8 mmol, Preparation 8, Step 1) in THF (65 mL) at −78° C.under a nitrogen atmosphere was added dropwise n-butyllithium (10 mL of2.5 M in hexanes, 25 mmol). The resulting mixture was stirred at thistemperature for 1 hour, then bromine (5.0 g, 1.6 mL, 31 mmol) was slowlyadded over 10 minutes. The mixture was stirred at this temperature for 1hour. The dry ice bath was removed and the mixture was treated withsaturated aqueous NaHCO₃ (150 mL). The mixture was partitioned betweendichloromethane (150 mL) and water (100 mL). The layers were separatedand the aqueous layer was extracted with additional dichloromethane (150mL). The combined organic layers were dried over anhydrous Na₂SO₄,filtered and concentrated in vacuo. Silica gel chromatography (0-20%ethyl acetate/heptane) provided2-bromo-3-fluoro-1-(methoxymethoxy)-4-(trifluoromethoxy)benzene (6.51 g,98%) as a colorless oil. ¹H NMR (300 MHz, CDCl₃) δ 7.22 (ddd, J=9.2,8.2, 1.0 Hz, 1H), 6.96 (dd, J=9.4, 2.1 Hz, 1H), 5.26 (s, 2H), 3.52 (s,3H) ppm. ¹⁹F NMR (282 MHz, CDCl₃) δ −59.15-−59.39 (m, 3F), −117.43 (d,J=6.1 Hz, 1F) ppm.

Step 2:2-cyclopropyl-3-fluoro-1-(methoxymethoxy)-4-(trifluoromethoxy)benzene

A solution of2-bromo-3-fluoro-1-(methoxymethoxy)-4-(trifluoromethoxy)benzene (11.38g, 33.53 mmol) in toluene (165 mL) was degassed by nitrogen bubbling for1 hour, then cyclopropylboronic acid (6.0 g, 70 mmol), K₃PO₄ (18.3 g,102 mmol), tricyclohexylphosphine tetrafluoroborate (2.5 g, 6.8 mmol),palladium (II) acetate (770 mg, 3.43 mmol) and nitrogen-degassed water(16.5 mL) were added. The mixture was stirred at 100° C. for 10 hours.The mixture was cooled to room temperature and filtered through a pad ofCelite, rinsing with additional ethyl acetate (100 mL). The filtrate wasdried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. Silicagel chromatography (0-15% ethyl acetate/heptane), followed by reversephase chromatography (5-95% acetonitrile/0.1% aqueous formic acid)provided2-cyclopropyl-3-fluoro-1-(methoxymethoxy)-4-(trifluoromethoxy)benzene(6.62 g, 70%) as a colorless oil. ¹H NMR (300 MHz, CDCl₃) δ 7.07-6.98(m, 1H), 6.82 (dd, J=9.2, 1.9 Hz, 1H), 5.19 (s, 2H), 3.50 (s, 3H),1.94-1.83 (m, 1H), 1.03-0.90 (m, 4H) ppm. ¹⁹F NMR (282 MHz, CDCl₃) δ−59.03-−59.39 (m, 3F), −131.68-−131.95 (m, 1F) ppm.

Step 4: 2-cyclopropyl-3-fluoro-4-(trifluoromethoxy)phenol

To a mixture of2-cyclopropyl-3-fluoro-1-(methoxymethoxy)-4-(trifluoromethoxy)benzene(6.41 g, 22.9 mmol) in THF (80 mL) at room temperature was addedconcentrated aqueous HCl (3.3 mL of 12 M, 39.600 mmol) dropwise. Themixture was stirred at 40° C. for 5 hours, and then at room temperatureovernight. Approximately half of the THF was removed under reducedpressure, and then the mixture was partitioned between water (200 mL)and dichloromethane (150 mL). The layers were separated and the aqueouslayer was extracted with additional dichloromethane (2×100 mL). Thecombined organic layers were dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. Silica gel chromatography (0-30% ethylacetate/heptane) followed by reverse phase chromatography (5-95%acetonitrile/0.1% aqueous formic acid) provided a product residue whichwas partitioned between water and dichloromethane. The aqueous layer wasextracted with additional dichloromethane (3×), and the combined organiclayers were dried over anhydrous Na₂SO₄, filtered and concentrated invacuo to provide 2-cyclopropyl-3-fluoro-4-(trifluoromethoxy)phenol (3.76g, 68%) as a pale yellow oil. ESI-MS m z calc. 236.05, found 235.0(M−1)⁻; LC/MS retention time (Method M): 3.02 minutes. ¹H NMR (300 MHz,CDCl₃) δ 7.07 (t, J=8.7 Hz, 1H), 6.64 (dd, J=9.1, 2.1 Hz, 1H), 5.75 (s,1H), 1.66-1.56 (m, 1H), 1.14-1.06 (m, 2H), 0.78-0.70 (m, 2H) ppm. ¹⁹FNMR (282 MHz, CDCl₃) δ −59.36 (d, J=6.1 Hz, 3F), −129.15-−129.33 (m, 1F)ppm.

Preparation 10 2-ethoxy-4-(trifluoromethoxy)phenol Step 1:1-bromo-2-ethoxy-4-(trifluoromethoxy)benzene

To a mixture of 2-bromo-5-(trifluoromethoxy)phenol (5.2 g, 20 mmol) andiodoethane (1.64 mL, 20.5 mmol) in DMF (20 mL) was added K₂CO₃ (3.38 g,24.5 mmol). The mixture was stirred at room temperature overnight.Additional iodoethane (500 μL, 6.25 mmol) was added and the mixturestirred for 90 minutes, then allowed to stand overnight. The mixture wasdiluted with water (50 mL) and extracted with MTBE (3×50 mL). Thecombined organic extracts were washed with water (3×50 mL) and brine (50mL), dried (phase separation cartridge) and concentrated in vacuo toafford 1-bromo-2-ethoxy-4-(trifluoromethoxy)benzene (5.587 g, 97%) as apale yellow oil. ¹H NMR (500 MHz, DMSO-d₆) δ 7.70 (d, J=8.7 Hz, 1H),7.15-7.10 (m, 1H), 6.91 (ddq, J=8.7, 2.5, 1.2 Hz, 1H), 4.16 (q, J=7.0Hz, 2H), 1.36 (t, J=7.0 Hz, 3H) ppm.

Step 2: [2-ethoxy-4-(trifluoromethoxy)phenyl]boronic acid

A three-necked flask with a thermometer and nitrogen inlet was chargedunder a nitrogen atmosphere with THF (150 mL) and was cooled to −78° C.n-Butyllithium (27 mL of 2.5 M in hexanes, 67.5 mmol) was added over 5minutes while maintaining the internal temperature below −60° C.1-Bromo-2-ethoxy-4-(trifluoromethoxy)benzene (16.9 g, 59.3 mmol) wasadded dropwise over 5 minutes while maintaining temperature below −65°C. The solution was stirred for 15 minutes, then treated with trimethylborate (9 mL, 80 mmol) over 10 minutes, keeping the temperature below−65° C. After complete addition, the mixture was stirred at −78° C. foran additional hour. The mixture was treated dropwise with 2 M aqueousHCl (32 mL, 64 mmol) until pH=1 and the mixture was allowed to warm toroom temperature. The aqueous phase was separated and extracted withMTBE (2×150 mL). The combined organic phases were washed with brine,dried over MgSO₄ and concentrated in vacuo to afford[2-ethoxy-4-(trifluoromethoxy)phenyl]boronic acid (14.1 g, 95%) as anoff-white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 7.79 (s, 2H), 7.61 (d,J=8.0 Hz, 1H), 6.96-6.88 (m, 2H), 4.10 (q, J=7.0 Hz, 2H), 1.36 (t, J=6.9Hz, 3H) ppm. ¹⁹F NMR (376 MHz, DMSO) δ −56.48 ppm.

Step 3: 2-ethoxy-4-(trifluoromethoxy)phenol

[2-Ethoxy-4-(trifluoromethoxy)phenyl]boronic acid (14.1 g, 54.5 mmol)was dissolved in THF (150 mL) and water (150 mL). Sodium perboratemonohydrate (16.7 g, 167 mmol) was added in one portion, resulting in anexotherm to 37° C. after the addition. The mixture was stirred at roomtemperature for 20 minutes. The resulting white suspension was filtered,and the solid washed with water and MTBE. The filtrate phases wereseparated and the aqueous phase was extracted again with MTBE (100 mL).The combined organic phases were dried (phase separation cartridge) andconcentrated in vacuo to afford 2-ethoxy-4-(trifluoromethoxy)phenol(12.4 g, 100%) as a yellow-orange oil. ¹H NMR (400 MHz, DMSO-d₆) δ 9.25(s, 1H), 6.90 (d, J=2.7 Hz, 1H), 6.83 (d, J=8.7 Hz, 1H), 6.78-6.70 (m,1H), 4.04 (q, J=7.0 Hz, 2H), 1.33 (t, J=7.0 Hz, 3H) ppm. ¹⁹F NMR (376MHz, DMSO) δ −57.17 ppm.

Preparation 11 3,4-difluoro-2-methyl-phenol Step 1:1-bromo-3,4-difluoro-2-methyl-benzene

To a stirring suspension of 1,2-difluoro-3-methyl-benzene (10 g, 78mmol) and iron powder (1.9 g, 7.5 mmol) in CHCl₃ (50 mL) under nitrogenwas added Br₂ (12.1 g, 75.7 mmol) in a single portion. The mixture wasstirred at room temperature for 19 hours, and then concentrated in vacuoto a volume of −25 mL. The residue was purified using silica gel columnchromatography (100% hexanes) to provide1-bromo-3,4-difluoro-2-methyl-benzene (15 g, 93%) as a clear oil. ¹H NMR(400 MHz, CDCl₃) δ 7.27 (ddd, J=8.9, 4.6, 2.2 Hz, 1H), 7.03-6.76 (m,1H), 2.35 (s, 3H) ppm.

Step 2: 3,4-difluoro-2-methyl-phenol

A mixture of 1-bromo-3,4-difluoro-2-methyl-benzene (22 g, 106 mmol),Me₄tButylXphos (1.51 g, 3.14 mmol) and KOH (18.2 g, 324 mmol) in dioxane(63 mL) and water (63 mL) was degassed with nitrogen bubbling for 10minutes. Pd₂dba₃ (1.5 g, 1.6 mmol) was added and the mixture purged withnitrogen (3×). The mixture was stirred at 90° C. for 5 hours, and thendiluted with water (100 mL) and washed with ether (3×80 mL). The aqueouslayer was acidified with 3 M aqueous HCl to pH 1-2, and then extractedwith ether (3×100 mL). The organic extracts were combined and washedwith saturated aqueous NaHCO₃ (3×50 mL) and brine (50 mL), dried overNa₂SO₄, filtered and concentrated in vacuo to provide3,4-difluoro-2-methyl-phenol (16.9 g, 85%) as a light orange oil. ESI-MSm z calc. 144.04, found 143.3 (M−1)⁻; LC/MS retention time (Method M):2.37 minutes. ¹H NMR (300 MHz, CDCl₃) δ 6.85 (q, J=9.1 Hz, 1H),6.52-6.40 (m, 1H), 5.10-4.94 (m, 1H), 2.23-2.13 (m, 3H) ppm. ¹⁹F NMR(282 MHz, CDCl₃) δ −139.60 (dd, J=21.4, 6.1 Hz, 1F), −148.15 (dd,J=21.4, 6.1 Hz, 1F) ppm.

Example 14-[[2-[(6-chloro-2-methoxy-3-pyridyl)oxy]-5-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(1)

Step 1: 2-bromo-N-(2-cyano-4-pyridyl)-5-(trifluoromethyl)benzamide

A solution of 2-bromo-5-(trifluoromethyl)benzoic acid (1 g, 3.7173 mmol)and 4-aminopyridine-2-carboxamide (515 mg, 3.7553 mmol) in pyridine(20.000 mL) was cooled to −10° C. followed by drop-wise addition ofPOCl₃ (855.40 mg, 520 μL, 5.5788 mmol) with stirring. Stirring wascontinued for 90 minutes at −10° C. The reaction was then quenched withwater (20 mL) and extracted with ethyl acetate (100 mL). The organiclayer was washed with water (30 mL×3) and brine, dried over anhydrousMgSO₄ and filtered. The filtrate was concentrated under vacuo, and theresidue dried under vacuum to afford2-bromo-N-(2-cyano-4-pyridyl)-5-(trifluoromethyl)benzamide (1.34 g, 88%)as an orange solid. ESI-MS m/z calc. 368.9725, found 369.9 (M+1)⁺;Retention time: 5.27 minutes. LCMS Method: Merckmillipore ChromolithSpeedROD C18 column (50×4.6 mm) and a dual gradient run from 5-100%mobile phase B over 12 minutes. Mobile phase A=water (0.1% CF3CO2H).Mobile phase B=acetonitrile (0.1% CF3CO2H); LCMS Method Detail: null.

Step 2:4-[[2-bromo-5-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide

To a solution of mixture of2-bromo-N-(2-cyano-4-pyridyl)-5-(trifluoromethyl)benzamide (13.01 g,31.635 mmol) and K₂CO₃ (6.56 g, 47.465 mmol) in DMSO (390.30 mL) wasadded H₂O₂ (107.61 mL of 30% w/v, 949.05 mmol) dropwise at 10° C. withstirring. The reaction mixture was allowed to warm to ambienttemperature and stirred for a further 30 minutes. The reaction mixturewas then cooled to 4° C., diluted with ethyl acetate (600 mL) andquenched with 10% aqueous Na₂S₂O₃ (500 mL). The organic layer was washedwith 10% aq. Na₂S₂O₃ (250 mL), water (250 mL×3), brine (250 mL), driedover anhydrous MgSO₄ and filtered. The filtrate was concentrated underreduced pressure to afford4-[[2-bromo-5-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(9.28 g, 72%) as an orange solid. ESI-MS m/z calc. 386.983, found 388.2(M+1)⁺; Retention time: 1.83 minutes. 1H NMR (500 MHz, DMSO-d6) δ 11.20(s, 1H), 8.57 (d, J=5.5 Hz, 1H), 8.38 (d, J=2.1 Hz, 1H), 8.11 (dd,J=8.4, 2.6 Hz, 2H), 8.02 (d, J=8.4 Hz, 1H), 7.88-7.81 (m, 2H), 7.67 (s,1H) ppm. LCMS Method: Water Cortex 2.7u C18 (3.0 mm×50 mm), Temp: 55c;Flow: 1.2 mL/minutes; MP: 100% water with 0.1% trifluoroacetic (TFA)acid then 100% acetonitrile with 0.1% TFA acid, grad:5% to 100% B over 4min, with stay at 100% B for 0.5 min, equilibration to 5% B over 1.5min; LCMS Method Detail: null.

Step 3:4-[[2-[(6-chloro-2-methoxy-3-pyridyl)oxy]-5-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(1)

A solution of4-[[2-bromo-5-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide (40mg, 0.1031 mmol) in DMSO (0.25 mL) was added to6-chloro-2-methoxy-pyridin-3-ol (32.90 mg, 0.2062 mmol) followed by CsF(62.65 mg, 15.22 μL, 0.4124 mmol). The reaction mixture was capped andallowed to stir at 110° C. for 40 minutes. The product was purified byHPLC to provide4-[[2-[(6-chloro-2-methoxy-3-pyridyl)oxy]-5-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(20.5 mg, 42%) was obtained. ESI-MS m/z calc. 466.06558, found 467.05(M+1)⁺; Retention time (Method B): 1.77 minutes. ¹H NMR (400 MHz,DMSO-d₆) δ 11.08 (s, 1H), 8.54 (d, J=5.5 Hz, 1H), 8.33 (d, J=2.1 Hz,11), 8.12 (d, J=2.8 Hz, 1), 8.06 (d, J 2.3 Hz, 1), 7.88 (dd, J 5.5, 2.2Hz, 1H), 7.82 (dd, J 8.8, 2.4 Hz, 1H), 7.72 (d, J=8.1 Hz, 1), 7.66 (s,11), 7.19 (d, J=8.2 Hz, 1H), 7.05 (d, J=8.8 Hz, 1), 3.83 (s, 3H).

The compounds set forth in Table 1 were prepared by methods analogous tothe preparation of compound 1 in Example 1.

TABLE 1 Additional Compounds Prepared by Methods Analogous to Example 1.Cmpd No. Compound Name LC/MS NMR (shifts in ppm) 24-[[2-(3-chloro-4-isopropoxy- ESI-MS m/z ¹H NMR (400 MHz, DMSO-d₆) δ11.05 phenoxy)-5- calc. 493.10162, (s, 1H), 8.54 (d, J = 5.5 Hz, 1H),8.33 (d, (trifluoromethyl)benzoyl]ami- found 493.95 J = 2.2 Hz, 1H),8.12 (s, 1H), 8.04 (d, J = no]pyridine-2-carboxamide (M + 1)+; 2.3 Hz,1H), 7.89 (dd, J = 5.5, 2.2 Hz, Retention time 1H), 7.85 (dd, J = 9.0,2.4 Hz, 1H), 7.67 (Method B): (s, 1H), 7.40 (d, J = 2.8 Hz, 1H), 7.26(d, 1.96 minutes J = 9.1 Hz, 1H), 7.18 (dd, J = 8.9, 2.9 Hz, 1H), 7.05(d, J = 8.8 Hz, 1H), 4.63 (p, J = 6.0 Hz, 1H), 1.29 (d, J = 6.0 Hz, 6H).3 4-[[2-(4-fluoro-3-methyl- ESI-MS m/z ¹H NMR (400 MHz, DMSO-d₆) δ 11.09phenoxy)-5- calc. 433.10495, (s, 1H), 8.54 (d, J = 5.5 Hz, 1H), 8.33 (d,(trifluoromethyl)benzoyl]ami- found 434.05 J = 2.1 Hz, 1H), 8.13 (d, J =2.8 Hz, 1H), no]pyridine-2-carboxamide (M + 1)+; 8.05 (d, J = 2.3 Hz,1H), 7.89 (dd, J = Retention time 5.5, 2.2 Hz, 1H), 7.85 (dd, J = 8.8,2.4 (Method B): Hz, 1H), 7.68 (d, J = 2.7 Hz, 1H), 7.24 1.82 minutes;(t, J = 9.0 Hz, 1H), 7.18 (dd, J = 6.4, 3.0 Hz, 1H), 7.08 (dt, J = 8.2,3.6 Hz, 1H), 7.02 (d, J = 8.7 Hz, 1H), 2.23 (d, J = 1.9 Hz, 3H). 44-[[2-(4-fluoro-2-methyl- ESI-MS m/z ¹H NMR (400 MHz, DMSO-d₆) δ 11.13phenoxy)-5- calc. 433.10495, (s, 1H), 8.55 (d, J = 5.5 Hz, 1H), 8.36 (d,(trifluoromethyl)benzoyl]ami- found 434.1 J = 2.1 Hz, 1H), 8.14 (s, 1H),8.06 (d, J = no]pyridine-2-carboxamide (M + 1)+; 2.3 Hz, 1H), 7.89 (dd,J = 5.5, 2.2 Hz, Retention time 1H), 7.82 (dd, J = 8.8, 2.4 Hz, 1H),7.69 (Method B): (s, 1H), 7.23 (ddd, J = 15.8, 9.1, 4.1 Hz, 1.81minutes; 2H), 7.14 (td, J = 8.5, 3.1 Hz, 1H), 6.85 (d, J = 8.8 Hz, 1H),2.15 (s, 3H). 5 4-[[2-(2-chloro-4-fluoro- ESI-MS m/z ¹H NMR (400 MHz,DMSO-d₆) δ 11.16 phenoxy)-5- calc. 453.05032, (s, 1H), 8.55 (d, J = 5.5Hz, 1H), 8.36 (d, (trifluoromethyl)benzoyl]ami- found 454.0 J = 2.1 Hz,1H), 8.15 (d, J = 2.6 Hz, 1H), no]pyridine-2-carboxamide (M + 1)+; 8.10(d, J = 2.3 Hz, 1H), 7.91 (dd, J = Retention time 5.6, 2.2 Hz, 1H), 7.86(dd, J = 8.7, 2.4 (Method B): Hz, 1H), 7.69 (dd, J = 8.3, 3.0 Hz, 2H),1.78 minutes; 7.48 (dd, J = 9.1, 5.2 Hz, 1H), 7.37 (td, J = 8.5, 3.0 Hz,1H), 6.94 (d, J = 8.7 Hz, 1H). 6 4-[[2-(3,4-difluorophenoxy)-5- ESI-MSm/z ¹H NMR (400 MHz, DMSO-d₆) δ 11.11 (trifluoromethyl)benzoyl]ami-calc. 437.0799, (s, 1H), 8.54 (d, J = 5.5 Hz, 1H), 8.33 (d,no]pyridine-2-carboxamide found 438.0 J = 2.1 Hz, 1H), 8.13 (d, J = 2.7Hz, 1H), (M + 1)+; 8.09 (d, J = 2.3 Hz, 1H), 7.88 (dd, J = Retentiontime 8.6, 2.8 Hz, 2H), 7.68 (s, 1H), 7.55 (q, J = (Method B): 9.5 Hz,1H), 7.44 (ddd, J = 11.4, 6.8, 1.74 minutes; 2.9 Hz, 1H), 7.14 (d, J =8.7 Hz, 1H), 7.09 (d, J = 9.2 Hz, 1H). 7 4-[[2-(3-fluoro-4-isopropoxy-ESI-MS m/z ¹H NMR (400 MHz, DMSO-d₆) δ 11.06 phenoxy)-5- calc.477.13116, (s, 1H), 8.54 (d, J = 5.5 Hz, 1H), 8.33 (d,(trifluoromethyl)benzoyl]ami- found 478.15 J = 2.2 Hz, 1H), 8.12 (d, J =2.8 Hz, 1H), no]pyridine-2-carboxamide (M + 1)+; 8.05 (d, J = 2.3 Hz,1H), 7.91-7.81 (m, Retention time 2H), 7.67 (d, J = 2.9 Hz, 1H), 7.30-(Method B): 7.19 (m, 2H), 7.06 (d, J = 8.7 Hz, 1H), 1.88 minutes;7.04-6.97 (m, 1H), 4.58 (p, J = 6.1 Hz, 1H), 1.27 (d, J = 6.1 Hz, 6H). 84-[[2-(4-fluoro-2-methoxy- ESI-MS m/z ¹H NMR (400 MHz, DMSO-d₆) δ 11.04phenoxy)-5- calc. 449.09988, (s, 1H), 8.55 (d, J = 5.4 Hz, 1H), 8.35 (d,(trifluoromethyl)benzoyl]ami- found 450.05 J = 2.1 Hz, 1H), 8.12 (d, J =2.9 Hz, 1H), no]pyridine-2-carboxamide (M + 1)+; 8.02 (d, J = 2.3 Hz,1H), 7.92 (dd, J = Retention time 5.5, 2.2 Hz, 1H), 7.79 (dd, J = 8.8,2.5 (Method B): Hz, 1H), 7.67 (d, J = 2.9 Hz, 1H), 7.36 1.76 minutes;(dd, J = 8.8, 5.9 Hz, 1H), 7.17 (dd, J = 10.7, 3.0 Hz, 1H), 6.89 (td, J= 8.5, 2.9 Hz, 1H), 6.81 (d, J = 8.8 Hz, 1H), 3.75 (s, 3H). 94-[[2-(4-isopropoxyphenoxy)- ESI-MS m/z ¹H NMR (400 MHz, DMSO-d₆) δ11.06 5- calc. 459.1406, (s, 1H), 8.54 (d, J = 5.5 Hz, 1H), 8.34 (d,(trifluoromethyl)benzoyl]ami- found 460.15 J = 2.2 Hz, 1H), 8.12 (d, J =3.3 Hz, 1H), no]pyridine-2-carboxamide (M + 1)+; 8.02 (d, J = 2.3 Hz,1H), 7.90 (dd, J = Retention time 5.6, 2.2 Hz, 1H), 7.83 (dd, J = 8.8,2.5 (Method B): Hz, 1H), 7.67 (d, J = 2.8 Hz, 1H), 7.16 1.89 minutes;(d, J = 9.0 Hz, 2H), 7.00 (d, J = 9.0 Hz, 2H), 6.95 (d, J = 8.8 Hz, 1H),4.58 (p, J = 6.1 Hz, 1H), 1.26 (d, J = 5.9 Hz, 6H). 104-[[2-[(4-fluoro-2,3- ESI-MS m/z ¹H NMR (400 MHz, DMSO-d₆) δ 11.07dihydrobenzofuran-7-yl)oxy]- calc. 461.09988, (s, 1H), 8.55 (d, J = 5.5Hz, 1H), 8.35 (d, 5- found 462.05 J = 2.1 Hz, 1H), 8.12 (d, J = 2.8 Hz,1H), (trifluoromethyl)benzoyl]ami- (M + 1)+; 8.02 (d, J = 2.3 Hz, 1H),7.91 (dd, J = no]pyridine-2-carboxamide Retention time 5.6, 2.2 Hz, 1H),7.82 (dd, J = 8.9, 2.4 (Method B): Hz, 1H), 7.67 (d, J = 2.9 Hz, 1H),7.14 1.77 minutes (dd, J = 9.0, 4.7 Hz, 1H), 6.95 (d, J = 8.8 Hz, 1H),6.78 (t, J = 8.5 Hz, 1H), 4.63 (t, J = 8.7 Hz, 2H), 3.29 (t, J = 8.7 Hz,2H). 11 4-[[2-(3-chloro-4-fluoro- ESI-MS m/z ¹H NMR (400 MHz, DMSO-d₆) δ11.10 phenoxy)-5- calc. 453.05032, (s, 1H), 8.54 (d, J = 5.5 Hz, 1H),8.33 (d, (trifluoromethyl)benzoyl]ami- found 454.05 J = 2.1 Hz, 1H),8.13 (s, 1H), 8.09 (d, J = no]pyridine-2-carboxamide (M + 1)+; 2.3 Hz,1H), 7.91-7.84 (m, 2H), 7.68 Retention time (s, 1H), 7.58-7.47 (m, 2H),7.27 (dt, J = (Method B): 9.0, 3.5 Hz, 1H), 7.14 (d, J = 8.8 Hz, 1.82minutes; 1H). 12 4-[[2-(3-fluoro-2-methoxy- ESI-MS m/z ¹H NMR (400 MHz,DMSO-d₆) δ 11.16 phenoxy)-5- calc. 449.09988, (s, 1H), 8.55 (d, J = 5.5Hz, 1H), 8.38 (d, (trifluoromethyl)benzoyl]ami- found 450.05 J = 2.1 Hz,1H), 8.15 (s, 1H), 8.09 (d, J = no]pyridine-2-carboxamide (M + 1)+; 2.3Hz, 1H), 7.90 (dd, J = 5.6, 2.2 Hz, Retention time 1H), 7.85 (dd, J =8.9, 2.4 Hz, 1H), 7.69 (Method B): (s, 1H), 7.28-7.16 (m, 2H), 7.10 (dd,J = 1.74 minutes; 7.9, 2.2 Hz, 1H), 7.00 (d, J = 8.7 Hz, 1H), 3.77 (s,3H). 13 4-[[2-[4- ESI-MS m/z ¹H NMR (400 MHz, DMSO-d₆) δ 11.05(cyclohexoxy)phenoxy]-5- calc. 499.1719, (s, 1H), 8.53 (d, J = 5.5 Hz,1H), 8.33 (d, (trifluoromethyl)benzoyl]ami- found 500.1 J = 2.1 Hz, 1H),8.11 (d, J = 2.7 Hz, 1H), no]pyridine-2-carboxamide (M + 1)+; 8.02 (d, J= 2.4 Hz, 1H), 7.90 (dd, J = Retention time 5.8, 2.2 Hz, 1H), 7.82 (dd,J = 8.9, 2.5 (Method B): Hz, 1H), 7.66 (s, 1H), 7.15 (d, J = 8.9 2.11minutes Hz, 2H), 7.01 (d, J = 9.1 Hz, 2H), 6.95 (d, J = 8.8 Hz, 1H),4.39-4.19 (m, 0H), 1.97-1.85 (m, 2H), 1.76-1.66 (m, 2H), 1.60-1.49 (m,1H), 1.45-1.25 (m, 5H). 14 4-[[2-(3-cyclohexylphenoxy)- ESI-MS m/z ¹HNMR (400 MHz, DMSO-d₆) δ 11.07 5- calc. 483.17697, (s, 1H), 8.52 (d, J =5.5 Hz, 1H), 8.31 (s, (trifluoromethyl)benzoyl]ami- found 484.1 1H),8.11 (s, 1H), 8.05 (d, J = 2.4 Hz, no]pyridine-2-carboxamide (M + 1)+;1H), 7.86 (d, J = 7.3 Hz, 2H), 7.66 (s, Retention time 1H), 7.35 (t, J =7.9 Hz, 1H), 7.09 (d, J = (Method B): 7.7 Hz, 1H), 7.07-7.02 (m, 2H),6.97 2.18 minutes (dd, J = 8.2, 2.5 Hz, 1H), 2.46 (m, 1H, obscured byDMSO), 1.70 (d, J = 36.7 Hz, 5H), 1.40-1.16 (m, 5H). 154-[[2-(5-chloro-2-methoxy- ESI-MS m/z ¹H NMR (400 MHz, DMSO-d₆) δ 11.00phenoxy)-5- calc. 465.0703, (s, 1H), 8.54 (d, J = 5.5 Hz, 1H), 8.35 (d,(trifluoromethyl)benzoyl]ami- found 466.1 J = 2.1 Hz, 1H), 8.12 (d, J =2.6 Hz, 1H), no]pyridine-2-carboxamide (M + 1)+; 8.03 (d, J = 2.4 Hz,1H), 7.90 (dd, J = Retention time 5.6, 2.2 Hz, 1H), 7.82 (dd, J = 8.8,2.4 (Method B): Hz, 1H), 7.67 (s, 1H), 7.42 (d, J = 2.6 1.84 minutes Hz,1H), 7.35 (dd, J = 8.9, 2.6 Hz, 1H), 7.24 (d, J = 8.9 Hz, 1H), 6.90 (d,J = 8.8 Hz, 1H), 3.74 (s, 3H). 16 4-[[2-(4-fluoro-3-methoxy- ESI-MS m/z¹H NMR (400 MHz, DMSO-d₆) δ 11.07 phenoxy)-5- calc. 449.09988, (s, 1H),8.54 (d, J = 5.5 Hz, 1H), 8.34 (d, (trifluoromethyl)benzoyl]ami- found450.0 J = 2.1 Hz, 1H), 8.11 (s, 1H), 8.05 (d, J =no]pyridine-2-carboxamide (M + 1)+; 2.3 Hz, 1H), 7.88 (dd, J = 5.6, 2.2Hz, Retention time 1H), 7.84 (dd, J = 9.0, 2.4 Hz, 1H), 7.67 (Method B):(s, 1H), 7.30 (dd, J = 11.2, 8.8 Hz, 1H), 1.74 minutes 7.10 (dd, J =7.4, 2.8 Hz, 1H), 7.04 (d, J = 8.7 Hz, 1H), 6.81-6.74 (m, 1H), 3.81 (s,3H). 17 4-[[2-(2,4-difluorophenoxy)-5- ESI-MS m/z ¹H NMR (400 MHz,DMSO-d₆) δ 11.16 (trifluoromethyl)benzoyl]ami- calc. 437.0799, (s, 1H),8.55 (d, J = 5.5 Hz, 1H), 8.35 (d, no]pyridine-2-carboxamide found 438.1J = 2.1 Hz, 1H), 8.13 (s, 1H), 8.08 (d, J = (M + 1)+; 2.3 Hz, 1H), 7.90(dd, J = 5.5, 2.2 Hz, Retention time 1H), 7.88-7.83 (m, 1H), 7.68 (s,1H), (Method B): 7.54 (td, J = 11.3, 10.1, 3.0 Hz, 1H), 7.48 1.72minutes (td, J = 9.2, 5.6 Hz, 1H), 7.22 (t, J = 9.3 Hz, 1H), 7.05 (d, J= 8.8 Hz, 1H).

Example 24-[[6-(2,3-difluoro-4-isopropoxy-phenoxy)-2-fluoro-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(18)

Step 1: methyl4-[[6-bromo-2-fluoro-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxylate

To an ice-cooled solution of 6-bromo-2-fluoro-3-(trifluoromethyl)benzoicacid (250 mg, 0.8711 mmol) in DCM (10 mL) was added DMF (5 μL, 0.06457mmol) oxalyl chloride (230 μL, 2.637 mmol) and the mixture was stirredand warmed to RT over 3.5 h. The reaction mixture was concentrated invacuo, dissolved in DCM (10 mL) and added drop-wise to a solution ofmethyl 4-aminopyridine-2-carboxylate (160 mg, 1.052 mmol) and TEA (610μL, 4.377 mmol) in DCM (10 mL) at 0° C. The resulting mixture wasstirred and warmed to ambient temperature over 18 h. The reactionmixture was quenched with water and the layers separated. The aqueouslayer was extracted with DCM (×2) and the combined organics extractswere dried (MgSO₄), filtered and concentrated in vacuo. The residue waspurified by column chromatography (0 to 75% EtOAc/Petroleum Ether) togive methyl4-[[6-bromo-2-fluoro-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxylate(98.1 mg, 27%) as a pale yellow solid. ESI-MS m/z calc. 419.97327, found423.0 (M+1)⁺; 421.0 (M−1)⁻; Retention time (Method E): 0.78 minutes. ¹HNMR (500 MHz, Chloroform-d) δ 8.76 (d, J=5.4 Hz, 1H), 8.21 (d, J=1.9 Hz,1H), 8.07 (dd, J=5.5, 2.1 Hz, 1H), 7.87 (s, 1H), 7.66-7.61 (m, 2H), 4.04(s, 3H); 19F NMR (471 MHz, Chloroform-d) 6-61.47 (d, J=12.9 Hz), −112.56(q, J=12.9 Hz) ppm.

Step 2:4-[[6-bromo-2-fluoro-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide

To a solution of methyl4-[[6-bromo-2-fluoro-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxylate(13.46 g, 31.961 mmol) in MeCN (160 mL) was added NH₄Cl (600 mg, 11.217mmol) and NH₄OH (153.00 g, 170 mL of 28% w/v, 4.3657 mol) with stirringat ambient temperature. The reaction mixture was stirred at ambienttemperature overnight then diluted with ethyl acetate (400 mL) andwashed with water (150 mL×2), brine, dried over anhydrous MgSO₄ andfiltered. Filtrate was evaporated, residue was subjected to flashpurification (330 g SG column; dry loading; gradient 0->90%EtOAc/hexane/2%(7N NH₃/MeOH) in 60 minutes) to afford4-[[6-bromo-2-fluoro-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(8.266 g, 60%) as off-white solid. ESI-MS m/z calc. 404.9736, found406.0 (M+1)⁺; Retention time: 1.87 minutes. 1H NMR (500 MHz, DMSO-d6) δ11.53 (s, 1H), 8.60 (d, J=5.4 Hz, 1H), 8.35 (d, J=2.1 Hz, 1H), 8.14 (s,1H), 7.98-7.85 (m, 2H), 7.81 (dd, J=5.4, 2.2 Hz, 1H), 7.70 (s, 1H) ppm.LCMS Method: Water Cortex 2.7u C18 (3.0 mm×50 mm), Temp: 55c; Flow: 1.2mL/minutes; MP: 100% water with 0.1% trifluoroacetic (TFA) acid then100% acetonitrile with 0.10% TFA acid, grad:5% to 100% B over 4 min,with stay at 100% B for 0.5 min, equilibration to 5% B over 1.5 min;LCMS Method Detail: null.

Step 3:4-[[6-(2,3-difluoro-4-isopropoxy-phenoxy)-2-fluoro-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(18)

A mixture of4-[[6-bromo-2-fluoro-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(50 mg, 0.1231 mmol), 2,3-difluoro-4-isopropoxy-phenol (23.16 mg, 0.1231mmol), Cs₂CO₃ (80.22 mg, 0.2462 mmol), CuI (14.07 mg, 0.07386 mmol), andDMF (1.000 mL), was stirred at 100° C. for 1 hour. The reaction wasdiluted with DMSO (500 uL), filtered, and purified by reverse phase HPLC(gradient of 10-99% acetonitrile in water containing HCl as a modifier)to give4-[[6-(2,3-difluoro-4-isopropoxy-phenoxy)-2-fluoro-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(23.8 mg, 37%) as a white solid. ESI-MS m/z calc. 513.1123, found 513.9(M+1)⁺; Retention time (Method B): 1.77 minutes. ¹H NMR (400 MHz,DMSO-d6) δ 11.54 (s, 1H), 8.57 (d, J=5.5 Hz, 1H), 8.33 (d, J=2.1 Hz,1H), 8.14 (s, 1H), 7.86 (dd, J=10.5, 6.9 Hz, 2H), 7.69 (s, 1H),7.31-7.06 (m, 2H), 6.95 (d, J=8.9 Hz, 1H), 4.67 (hept, J=6.1 Hz, 1H),1.30 (d, J=6.0 Hz, 6H) ppm.

The compounds set forth in Table 2 were prepared by methods analogous tothe preparation of compound 18 and Example 2.

TABLE 2 Additional Compounds Prepared by Methods Analogous to Example 2.Cmpd No. Compound Name LC/MS NMR (shifts in ppm) 19 4-[[6-(4-ethoxy-2,3-ESI-MS m/z ¹H NMR (400 MHz, DMSO-d₆) δ 11.54 difluoro-phenoxy)-2- calc.499.09668, (s, 1H), 8.57 (d, J = 5.5 Hz, 1H), 8.32 (s, fluoro-3- found499.9 1H), 8.14 (s, 1H), 7.93-7.78 (m, 2H), (trifluoromethyl)benzoyl](M + 1)+; 7.70 (s, 1H), 7.21 (t, J = 9.0 Hz, 1H), amino]pyridine-2-Retention time 7.10 (t, J = 8.9 Hz, 1H), 6.93 (d, J = 8.9 carboxamide(Method B): Hz, 1H), 4.15 (q, J = 7.0 Hz, 2H), 1.36 1.7 minutes (t, J =6.9 Hz, 3H). 20 4-[[6-(2-chloro-4-fluoro- ESI-MS m/z 1H NMR (400 MHz,DMSO-d6) δ 11.51 phenoxy)-2-fluoro-3- calc. 471.04092, (s, 1H), 8.58 (d,J = 5.5 Hz, 1H), 8.33 (s, (trifluoromethyl)benzoyl] found 472.04 1H),8.14 (s, 1H), 7.91-7.82 (m, 2H), amino]pyridine-2- (M + 1)+; 7.72 (dd, J= 8.4, 3.1 Hz, 2H), 7.51 (dd, carboxamide Retention time J = 9.1, 5.2Hz, 1H), 7.39 (td, J = 8.4, 3.0 (Method B): Hz, 1H), 6.75 (d, J = 8.9Hz, 1H). 1.61 minutes 21 4-[[2-fluoro-6-(4-fluoro- ESI-MS m/z ¹H NMR(400 MHz, DMSO-d₆) δ 11.53 3-methoxy-phenoxy)-3- calc. 467.09045, (s,1H), 8.58 (s, 1H), 8.34 (s, 1H), 8.16 (trifluoromethyl)benzoyl] found468.07 (s, 1H), 7.86 (t, J = 8.6 Hz, 2H), 7.72 (s, amino]pyridine-2-(M + 1)+; 1H), 7.33 (dd, J = 11.2, 8.8 Hz, 1H), carboxamide Retentiontime 7.12 (dd, J = 7.4, 2.8 Hz, 1H), 6.84 (d, (Method B): J = 8.9 Hz,1H), 6.80 (dt, J = 8.9, 3.2 1.56 minutes Hz, 1H), 3.83 (s, 3H). 224-[[2-fluoro-6-phenoxy- ESI-MS m/z ¹H NMR (400 MHz, DMSO-d₆) δ 11.58 3-calc. 419.0893, (s, 1H), 8.57 (d, J = 5.5 Hz, 1H), 8.34 (d,(trifluoromethyl)benzoyl] found 420.0 J = 2.2 Hz, 1H), 8.17 (s, 1H),7.92-7.83 amino]pyridine-2- (M + 1)+; (m, 2H), 7.73 (s, 1H), 7.50 (t, J= 7.9 Hz, carboxamide Retention time 2H), 7.31 (t, J = 7.4 Hz, 1H), 7.24(d, J = (Method C): 8.0 Hz, 2H), 6.80 (d, J = 8.9 Hz, 1H). 2.12 minutes23 4-[[6-(4-ethoxyphenoxy)- ESI-MS m/z 1H NMR (400 MHz, DMSO-d6) δ 11.532-fluoro-3- calc. 463.1155, (s, 1H), 8.57 (s, 1H), 8.34 (s, 1H), 8.16(trifluoromethyl)benzoyl] found 464.0 (s, 1H), 7.97-7.79 (m, 2H), 7.72(s, amino]pyridine-2- (M + 1)+; 1H), 7.17 (d, J = 9.0 Hz, 2H), 7.02 (d,J = carboxamide Retention time 9.0 Hz, 2H), 6.72 (d, J = 8.9 Hz, 1H),(Method B): 4.02 (q, J = 7.0 Hz, 2H), 1.32 (t, J = 7.0 1.66 minutes Hz,3H). 24 4-[[6-(3,4- ESI-MS m/z ¹H NMR (400 MHz, DMSO-d₆) δ 11.49difluorophenoxy)-2- calc. 455.07047, (s, 1H), 8.57 (d, J = 5.5 Hz, 1H),8.31 (s, fluoro-3- found 456.05 1H), 8.14 (s, 1H), 7.89 (t, J = 8.7 Hz,(trifluoromethyl)benzoyl] (M + 1)+; 1H), 7.83 (d, J = 5.5 Hz, 1H), 7.70(s, amino]pyridine-2- Retention time 1H), 7.57 (q, J = 9.5 Hz, 1H), 7.49(ddd, carboxamide (Method B): J = 10.5, 6.8, 3.0 Hz, 1H), 7.13 (d, J =1.58 minutes 9.4 Hz, 1H), 6.94 (d, J = 8.9 Hz, 1H). 254-[[6-(3-chloro-4-fluoro- ESI-MS m/z ¹H NMR (400 MHz, DMSO-d₆) δ 11.46phenoxy)-2-fluoro-3- calc. 471.04092, (s, 1H), 8.57 (d, J = 5.5 Hz, 1H),8.31 (d, (trifluoromethyl)benzoyl] found 472.04 J = 2.1 Hz, 1H), 8.13(s, 1H), 7.89 (t, J = amino]pyridine-2- (M + 1)+; 8.7 Hz, 1H), 7.82 (dd,J = 5.5, 2.2 Hz, carboxamide Retention time 1H), 7.69 (s, 1H), 7.60 (dd,J = 6.2, 2.9 (Method B): Hz, 1H), 7.55 (t, J = 9.0 Hz, 1H), 7.30 1.65minutes; (dt, J = 9.1, 3.5 Hz, 1H), 6.94 (d, J = 8.9 Hz, 1H). 264-[[2-fluoro-6-[[2- ESI-MS m/z 1H NMR (400 MHz, DMSO-d6) δ 11.61methyl-6- calc. 502.0876, (s, 1H), 8.56 (s, 1H), 8.30 (s, 1H), 8.16(trifluoromethyl)-3- found 503.08 (s, 1H), 7.94 (t, J = 8.6 Hz, 1H),7.87- pyridyl]oxy]-3- (M + 1)+; 7.75 (m, 3H), 7.72 (s, 1H), 7.10 (d, J =(trifluoromethyl)benzoyl] Retention time 8.8 Hz, 1H), 2.45 (s, 3H).amino]pyridine-2- (Method B): carboxamide 1.56 minutes; 274-[[6-(5-chloro-2- ESI-MS m/z ¹H NMR (400 MHz, DMSO-d₆) δ 11.44methoxy-phenoxy)-2- calc. 483.06088, (s, 1H), 8.58 (s, 1H), 8.35 (s,1H), 8.14 fluoro-3- found 484.06 (s, 1H), 7.90-7.78 (m, 2H), 7.70 (s,(trifluoromethyl)benzoyl] (M + 1)+; 1H), 7.43-7.37 (m, 2H), 7.26 (d, J =amino]pyridine-2- Retention time 8.7 Hz, 1H), 6.71 (d, J = 8.9 Hz, 1H),carboxamide (Method B): 3.76 (s, 3H). 1.63 minutes; 284-[[2-fluoro-6-(3-fluoro- ESI-MS m/z ¹H NMR (400 MHz, DMSO-d₆) δ 11.464-isopropoxy-phenoxy)- calc. 495.12173, (s, 1H), 8.57 (s, 1H), 8.32 (s,0H), 8.15 3- found 496.09 (s, 2H), 7.86 (t, J = 8.6 Hz, 2H), 7.71 (s,(trifluoromethyl)benzoyl] (M + 1)+; 1H), 7.33-7.19 (m, 2H), 7.02 (d, J =amino]pyridine-2- Retention time 9.6 Hz, 1H), 6.86 (d, J = 8.9 Hz, 1H),carboxamide (Method B): 4.60 (p, J = 6.1 Hz, 1H), 1.28 (d, J = 6.0 1.7minutes Hz, 6H). 29 4-[[6-(4-ethoxy-3-fluoro- ESI-MS m/z 1H NMR (400MHz, DMSO-d6) δ 11.49 phenoxy)-2-fluoro-3- calc. 481.1061, (s, 1H), 8.57(d, J = 5.5 Hz, 1H), 8.32 (d, (trifluoromethyl)benzoyl] found 481.9 J =2.2 Hz, 1H), 8.14 (s, 1H), 7.94-7.80 amino]pyridine-2- (M + 1)+; (m,2H), 7.70 (s, 1H), 7.34-7.14 (m, carboxamide Retention time 2H), 7.04(ddd, J = 9.0, 2.9, 1.5 Hz, 1H), (Method B): 6.83 (d, J = 8.9 Hz, 1H),4.10 (q, J = 6.9 1.67 minutes; Hz, 2H), 1.34 (t, J = 6.9 Hz, 3H). 304-[[2-fluoro-6-[(4-fluoro- ESI-MS m/z ¹H NMR (400 MHz, DMSO-d₆) δ 11.492,3-dihydrobenzofuran-7- calc. 479.09045, (s, 1H), 8.57 (s, 1H), 8.33(s, 1H), 8.14 yl)oxy]-3- found 480.1 (s, 1H), 7.88-7.79 (m, 2H), 7.70(s, (trifluoromethyl)benzoyl] (M + 1)+; 1H), 7.11 (dd, J = 9.0, 4.7 Hz,1H), 6.83- amino]pyridine-2- Retention time 6.73 (m, 2H), 4.65 (t, J =8.7 Hz, 2H), carboxamide (Method B): 3.30 (t, J = 8.7 Hz, 2H). 1.58minutes; 31 4-[[6-(3,4-difluoro-2- ESI-MS m/z ¹H NMR (400 MHz, DMSO-d₆)δ 11.57 methoxy-phenoxy)-2- calc. 485.08102, (s, 1H), 8.58 (d, J = 5.5Hz, 1H), 8.36 (d, fluoro-3- found 485.9 J = 2.1 Hz, 1H), 8.15 (s, 1H),7.89-7.79 (trifluoromethyl)benzoyl] (M + 1)+; (m, 2H), 7.71 (s, 1H),7.30 (q, J = 9.3 amino]pyridine-2- Retention time Hz, 1H), 7.19 (ddd, J= 9.3, 5.2, 2.1 Hz, carboxamide (Method B): 1H), 6.81 (d, J = 8.9 Hz,1H), 3.85 (d, 1.63 minutes; J = 1.2 Hz, 3H). 324-[[2-fluoro-6-(4-fluoro- ESI-MS m/z ¹H NMR (400 MHz, DMSO-d₆) δ 11.473-methyl-phenoxy)-3- calc. 451.09552, (s, 1H), 8.57 (s, 1H), 8.32 (s,1H), 8.14 (trifluoromethyl)benzoyl] found 452.09 (s, 1H), 7.91-7.82 (m,2H), 7.70 (s, 1H), amino]pyridine-2- (M + 1)+; 7.26 (t, J = 9.0 Hz, 1H),7.20 (dd, J = carboxamide Retention time 6.4, 3.0 Hz, 1H), 7.10 (dd, J =8.5, 4.1 (Method B): Hz, 1H), 6.82 (d, J = 8.9 Hz, 1H), 2.27- 1.65minutes; 2.20 (m, 3H). 33 4-[[6-(3-chloro-4- ESI-MS m/z ¹H NMR (400 MHz,DMSO-d₆) δ 11.46 isopropoxy-phenoxy)-2- calc. 511.0922, (s, 1H), 8.57(s, 1H), 8.32 (s, 1H), 8.14 fluoro-3- found 512.08 (s, 1H), 7.86 (t, J =8.7 Hz, 2H), 7.70 (s, (trifluoromethyl)benzoyl] (M + 1)+; 1H), 7.41 (d,J = 2.8 Hz, 1H), 7.27 (d, J = amino]pyridine-2- Retention time 9.1 Hz,1H), 7.20 (dd, J = 9.0, 2.9 Hz, carboxamide (Method B): 1H), 6.85 (d, J= 8.9 Hz, 1H), 4.64 (p, J = 1.78 minutes; 6.1 Hz, 1H), 1.29 (d, J = 6.0Hz, 6H). 34 4-[[2-fluoro-6-(3-fluoro- ESI-MS m/z ¹H NMR (400 MHz,DMSO-d₆) δ 11.53 2-methoxy-phenoxy)-3- calc. 467.09045, (s, 1H), 8.57(d, J = 5.5 Hz, 1H), 8.35 (s, (trifluoromethyl)benzoyl] found 468.071H), 8.14 (s, 1H), 7.90-7.80 (m, 2H), amino]pyridine-2- (M + 1)+; 7.70(s, 1H), 7.32-7.25 (m, 1H), 7.22 carboxamide Retention time (td, J =8.3, 5.9 Hz, 1H), 7.13 (d, J = 7.9 (Method B): Hz, 1H), 6.78 (d, J = 8.9Hz, 1H), 3.78 1.56 minutes (s, 3H). 35 4-[[6-[4- ESI-MS m/z ¹H NMR (400MHz, DMSO-d₆) δ 11.47 (cyclohexoxy)phenoxy]- calc. 517.1625, (s, 1H),8.57 (s, 1H), 8.32 (s, 1H), 8.13 2-fluoro-3- found 518.13 (s, 1H), 7.84(t, J = 8.6 Hz, 1H), 7.70 (s, (trifluoromethyl)benzoyl] (M + 1)+; 1H),7.19-7.10 (m, 2H), 7.02 (d, J = amino]pyridine-2- Retention time 9.0 Hz,2H), 6.75 (d, J = 8.9 Hz, 1H), carboxamide (Method B): 4.31 (m, 1H),1.91 (m, 2H), 1.71 (m, 1.9 minutes; 2H), 1.53 (m, 1H), 1.47-1.18 (m,5H). 36 4-[[6-[2-(1,1- ESI-MS m/z 1H NMR (400 MHz, DMSO-d6) δ 11.52difluoroethyl)-4-fluoro- calc. 501.09235, (s, 1H), 8.56 (s, 1H), 8.33(s, 1H), 8.12 phenoxy]-2-fluoro-3- found 501.9 (s, 1H), 7.94-7.77 (m,1H), 7.69 (s, (trifluoromethyl)benzoyl] (M + 1)+; 2H), 7.50 (ddd, J =12.2, 9.0, 4.2 Hz, amino]pyridine-2- Retention time 1H), 7.40 (dd, J =9.0, 4.6 Hz, 2H), 6.80 carboxamide (Method B): (d, J = 8.9 Hz, 1H), 1.90(t, J = 19.2 Hz, 1.69 minutes; 3H). 37 4-[[2-fluoro-6-(4- ESI-MS m/z 1HNMR (500 MHz, DMSO-d6) δ 11.49 isopropoxyphenoxy)-3- calc. 477.13116,(d, J = 1.9 Hz, 1H), 8.57 (d, J = 5.5 Hz, (trifluoromethyl)benzoyl]found 478.0 1H), 8.33 (d, J = 2.2 Hz, 1H), 8.23- amino]pyridine-2- (M +1)+; 8.04 (m, 1H), 8.00-7.79 (m, 2H), 7.69 carboxamide Retention time(d, J = 2.5 Hz, 1H), 7.25-7.09 (m, 2H), (Method B): 7.09-6.93 (m, 2H),6.86-6.66 (m, 1.75 minutes. 1H), 4.59 (hept, J = 5.8 Hz, 1H), 1.26 (d, J= 6.0 Hz, 6H). 38 4-[[6-(3-chloro-4-ethoxy- ESI-MS m/z 1H NMR (400 MHz,DMSO-d6) δ 11.49 phenoxy)-2-fluoro-3- calc. 497.07654, (s, 1H), 8.57 (d,J = 5.5 Hz, 1H), 8.32 (d, (trifluoromethyl)benzoyl] found 497.9 J = 2.1Hz, 1H), 8.15 (s, 1H), 7.91-7.79 amino]pyridine-2- (M + 1)+; (m, 2H),7.74-7.67 (m, 1H), 7.43 (d, J = carboxamide Retention time 2.1 Hz, 1H),7.22 (d, J = 2.3 Hz, 2H), (Method B): 6.82 (d, J = 8.9 Hz, 1H), 4.12 (q,J = 6.9 1.76 minutes; Hz, 2H), 1.35 (t, J = 6.9 Hz, 3H). 394-[[2-fluoro-3- ESI-MS m/z ¹H NMR (400 MHz, DMSO-d₆) δ 11.58(trifluoromethyl)-6-[[6- calc. 488.07193, (s, 1H), 8.71 (d, J = 2.7 Hz,1H), 8.56 (s, (trifluoromethyl)-3- found 489.04 1H), 8.28 (s, 1H), 8.13(s, 1H), 7.99 (m, pyridyl]oxy]benzoyl]ami- (M + 1)+; 2H), 7.90 (dd, J =8.6, 2.7 Hz, 1H), 7.79 no]pyridine-2- Retention time (s, 1H), 7.71 (s,1H), 7.23 (d, J = 8.8 Hz, carboxamide (Method B): 1H). 1.51 minutes 404-[[6-(3- ESI-MS m/z ¹H NMR (400 MHz, DMSO-d₆) δ 11.46cyclohexylphenoxy)-2- calc. 501.16754, (s, 1H), 8.56 (s, 1H), 8.32 (s,1H), 8.13 (s, fluoro-3- found 502.14 1H), 7.93-7.81 (m, 2H), 7.69 (s,1H), (trifluoromethyl)benzoyl] (M + 1)+; 7.38 (t, J = 7.8 Hz, 1H), 7.15(d, J = 7.7 amino]pyridine-2- Retention time Hz, 1H), 7.09-6.98 (m, 2H),6.81 (d, J = carboxamide (Method B): 8.9 Hz, 1H), 1.72 (dd, J = 32.4,11.2 Hz, 1.98 minutes 6H), 1.28 (dt, J = 52.2, 11.5 Hz, 5H). 414-[[6-[2-cyclopropyl-4- ESI-MS m/z 1H NMR (400 MHz, DMSO-d6) δ 11.53(trifluoromethoxy)phenoxy]- calc. 543.1029, (s, 1H), 8.57 (d, J = 5.5Hz, 1H), 8.33 (s, 2-fluoro-3- found 544.0 1H), 8.12 (s, 1H), 7.86 (d, J= 8.7 Hz, 2H), (trifluoromethyl)benzoyl] (M + 1)+; 7.68 (s, 1H), 7.29(d, J = 8.8 Hz, 2H), 7.02 amino]pyridine-2- Retention time (s, 1H), 6.73(d, J = 8.9 Hz, 1H), 1.97 (s, carboxamide (Method B): 1H), 0.88 (d, J =10.4 Hz, 2H), 0.70 (s, 1.93 minutes 2H). 42 4-[[6-(3,4-difluoro-2-ESI-MS m/z 1H NMR (400 MHz, DMSO-d6) δ 11.67 methyl-phenoxy)-2- calc.469.08612, (s, 1H), 8.58 (d, J = 5.5 Hz, 1H), 8.36 (s, fluoro-3- found470.0 1H), 8.19 (s, 1H), 7.86 (d, J = 12.4 Hz, (trifluoromethyl)benzoyl](M + 1)+; 2H), 7.74 (s, 1H), 7.41 (d, J = 9.5 Hz, 1H), amino]pyridine-2-Retention time 7.11 (d, J = 7.6 Hz, 1H), 6.76 (d, J = 8.9 carboxamide(Method B): Hz, 1H), 2.11 (s, 3H). 1.75 minutes 43 4-[[6-(4-chloro-2-ESI-MS m/z 1H NMR (400 MHz, DMSO-d6) δ 11.45 methoxy-phenoxy)-2- calc.483.06088, (s, 1H), 8.54 (s, 1H), 8.31 (s, 1H), 8.09 (s, fluoro-3- found484.0 1H), 7.73 (d, J = 73.8 Hz, 3H), 7.28 (d, J =(trifluoromethyl)benzoyl] (M + 1)+; 27.7 Hz, 2H), 7.09 (d, J = 8.5 Hz,1H), amino]pyridine-2- Retention time 6.66 (s, 1H), 3.78 (s, 3H).carboxamide (Method B): 1.73 minutes 44 4-[[2-fluoro-6-[2- ESI-MS m/z 1HNMR (400 MHz, DMSO-d6) δ 11.47 methoxy-4-(1,1,2,2,2- calc. 567.08405,(s, 1H), 8.55 (d, J = 5.4 Hz, 1H), 8.31 (s, pentafluoroethyl)phenoxy]-found 568.0 1H), 8.10 (s, 1H), 7.83 (d, J = 4.9 Hz, 2H), 3- (M + 1)+;7.66 (s, 1H), 7.47 (d, J = 8.4 Hz, 1H), 7.42- (trifluoromethyl)benzoyl]Retention time 7.30 (m, 2H), 6.78 (d, J = 8.9 Hz, 1H), amino]pyridine-2-(Method B): 3.83 (s, 3H). carboxamide 1.83 minutes 454-[[6-(2,6-dimethoxy-4- ESI-MS m/z 1H NMR (400 MHz, DMSO-d6) δ 11.34methyl-phenoxy)-2- calc. 493.1261, (s, 1H), 8.56 (d, J = 5.5 Hz, 1H),8.35 (s, fluoro-3- found 494.0 1H), 8.10 (s, 1H), 7.84 (s, 1H), 7.75 (s,(trifluoromethyl)benzoyl] (M + 1)+; 1H), 7.66 (s, 1H), 6.65 (s, 2H),6.54 (d, J = amino]pyridine-2- Retention time 8.9 Hz, 1H), 3.72 (s, 6H),2.33 (s, 3H). carboxamide (Method B): 1.71 minutes 46 4-[[2-fluoro-3-ESI-MS m/z 1H NMR (400 MHz, DMSO-d6) δ 11.55 (trifluoromethyl)-6- calc.473.06104, (s, 1H), 8.57 (d, J = 5.4 Hz, 1H), 8.32 (s, (2,4,6- found474.0 1H), 8.11 (s, 1H), 7.93-7.76 (m, 2H),trifluorophenoxy)benzoyl]ami- (M + 1)+; 7.68 (s, 1H), 7.52 (s, 2H), 7.00(d, J = 8.9 no]pyridine-2- Retention time Hz, 1H). carboxamide (MethodB): 1.55 minutes 47 4-[[6-(2,4-dichloro-6- ESI-MS m/z 1H NMR (400 MHz,DMSO-d6) δ 11.53 methyl-phenoxy)-2- calc. 501.027, (s, 1H), 8.59 (s,1H), 8.37 (s, 1H), 8.13 (s, fluoro-3- found 502.0 1H), 7.82 (d, J = 26.1Hz, 2H), 7.70 (s, (trifluoromethyl)benzoyl] (M + 1)+; 2H), 7.53 (s, 1H),6.60 (d, J = 8.9 Hz, 1H), amino]pyridine-2- Retention time 2.19 (s, 3H).carboxamide (Method B): 1.83 minutes 48 4-[[2-fluoro-6-(4-fluoro- ESI-MSm/z 1H NMR (400 MHz, DMSO-d6) δ 11.50 2,3-dimethyl-phenoxy)-3- calc.465.11118, (s, 1H), 8.57 (d, J = 5.5 Hz, 1H), 8.33 (s,(trifluoromethyl)benzoyl] found 466.0 1H), 8.11 (s, 1H), 7.82 (d, J =8.9 Hz, 2H), amino]pyridine-2- (M + 1)+; 7.67 (s, 1H), 7.10 (d, J = 23.4Hz, 2H), carboxamide Retention time 6.59 (d, J = 8.9 Hz, 1H), 2.17 (s,3H), 2.08 (Method B): (s, 3H). 1.74 minutes 49 4-[[2-fluoro-3- ESI-MSm/z 1H NMR (400 MHz, DMSO-d6) δ 11.56 (trifluoromethyl)-6- calc.473.06104, (s, 1H), 8.57 (d, J = 5.5 Hz, 1H), 8.32 (s, (2,3,4- found474.0 1H), 8.12 (s, 1H), 7.89 (s, 1H), 7.82 (s,trifluorophenoxy)benzoyl]ami- (M + 1)+; 1H), 7.68 (s, 1H), 7.45 (d, J =9.8 Hz, 1H), no]pyridine-2- Retention time 7.30 (s, 1H), 7.04 (d, J =8.9 Hz, 1H). carboxamide (Method B): 1.6 minutes 504-[[6-(4-chloro-2-methyl- ESI-MS m/z 1H NMR (400 MHz, DMSO-d₆) δ 11.50phenoxy)-2-fluoro-3- calc. 467.06598, (s, 1H), 8.57 (d, J = 5.5 Hz, 1H),8.32 (d, (trifluoromethyl)benzoyl] found 468.0 J = 2.1 Hz, 1H),8.23-8.03 (m, 1H), 7.94- amino]pyridine-2- (M + 1)+; 7.78 (m, 2H), 7.69(d, J = 2.6 Hz, 1H), carboxamide Retention time 7.48 (d, J = 2.6 Hz,1H), 7.37 (dd, J = 8.6, (Method B): 2.7 Hz, 1H), 7.20 (d, J = 8.6 Hz,1H), 6.71 1.86 minutes (d, J = 8.8 Hz, 1H), 2.13 (s, 3H). 514-[[6-(4-chloro-2-fluoro- ESI-MS m/z 1H NMR (400 MHz, DMSO-d6) δ 11.56phenoxy)-2-fluoro-3- calc. 471.04092, (s, 1H), 8.57 (d, J = 5.5 Hz, 1H),8.32 (d, (trifluoromethyl)benzoyl] found 472.0 J = 1.9 Hz, 1H), 8.13 (s,1H), 7.92-7.78 amino]pyridine-2- (M + 1)+; (m, 2H), 7.76-7.62 (m, 2H),7.51-7.35 carboxamide Retention time (m, 2H), 6.93 (d, J = 8.9 Hz, 1H).(Method B): 1.75 minutes 338 4-[[6-(3-chloro-4-fluoro- ESI-MS m/z ¹H NMR(400 MHz, DMSO-d₆) δ 11.54 2-methyl-phenoxy)-2- calc. 485.06, (s, 1H),8.57 (d, J = 5.4 Hz, 1H), 8.33 (d, fluoro-3- found 486.0 J = 2.2 Hz,1H), 8.13 (s, 1H), 7.87-7.79 (trifluoromethyl)benzoyl] (M + 1)⁺; LC/MS(m, 2H), 7.70 (s, 1H), 7.42 (t, J = 8.8 Hz, amino]pyridine-2- retentiontime 1H), 7.27 (dd, J = 9.1, 4.6 Hz, 1H), 6.74 carboxamide (Method C):(d, J = 8.9 Hz, 1H), 2.22 (s, 3H). (synthesized using 3- 2.47 minuteschloro-4-fluoro-2-methyl- phenol from Preparation 2) 3394-[[6-(2-chloro-3,4- ESI-MS m/z ¹H NMR (400 MHz, DMSO-d₆) δ 11.55difluoro-phenoxy)-2- calc. 489.03, (s, 1H), 8.57 (d, J = 5.5 Hz, 1H),8.32 (d, fluoro-3- found 490.0 J = 2.1 Hz, 1H), 8.14 (s, 1H), 7.88 (t, J= (trifluoromethyl)benzoyl] (M + 1)⁺; LC/MS 8.7 Hz, 1H), 7.84 (dd, J =5.5, 2.2 Hz, amino]pyridine-2- retention time 1H), 7.70 (s, 1H), 7.63(q, J = 9.4 Hz, 1H), carboxamide (Method C): 7.40-7.30 (m, 1H), 6.91 (d,J = 8.9 Hz, (synthesized using 2- 2.31 minutes 1H). chloro-3,4-difluoro-phenol from Preparation 3) 340 4-[[6-(2-cyclopropyl-3,6- ESI-MS m/z ¹HNMR (400 MHz, DMSO-d₆) δ 11.52 difluoro-phenoxy)-2- calc. 495.10, (s,1H), 8.58 (d, J = 5.5 Hz, 1H), 8.35 (d, fluoro-3- found 496.0 J = 2.2Hz, 1H), 8.12 (d, J = 2.7 Hz, 1H), (trifluoromethyl)benzoyl] (M + 1)⁺;LC/MS 7.89-7.81 (m, 2H), 7.68 (d, J = 2.9 Hz, amino]pyridine-2-retention time 1H), 7.36 (td, J = 9.5, 4.8 Hz, 1H), 7.21 carboxamide(Method C): (td, J = 9.8, 4.3 Hz, 1H), 6.77 (d, J = 8.9 (synthesizedusing 2- 2.43 minutes Hz, 1H), 1.80-1.69 (m, 1H), 0.93-0.76cyclopropyl-3,6-difluoro- (m, 4H). phenol from Preparation 4) 3414-[[6-[4- ESI-MS m/z ¹H NMR (400 MHz, DMSO-d₆) δ 11.47(difluoromethyl)-2- calc. 499.10, (d, J = 3.5 Hz, 1H), 8.56 (d, J = 5.5Hz, methoxy-phenoxy]-2- found 500.5 1H), 8.33 (d, J = 2.2 Hz, 1H), 8.12(d, J = fluoro-3- (M + 1)⁺; LC/MS 6.2 Hz, 1H), 7.88-7.75 (m, 2H), 7.68(s, (trifluoromethyl)benzoyl] retention time 1H), 7.46-7.34 (m, 2H),7.26 (dd, J = 8.2, amino]pyridine-2- (Method B): 1.8 Hz, 1H), 7.04 (t, J= 55.8 Hz, 1H), carboxamide 1.57 minutes 6.67 (d, J = 8.9 Hz, 1H), 3.80(s, 3H). (synthesized using 4- (difluoromethyl)-2- methoxy-phenol fromPreparation 5) 342 4-[[6-(2,3-dichloro-4- ESI-MS m/z ¹H NMR (400 MHz,DMSO-d₆) δ 11.55 fluoro-phenoxy)-2- calc. 505.00, (s, 1H), 8.58 (s, 1H),8.33 (s, 1H), 8.14 (s, fluoro-3- found 506.0 1H), 7.84 (m, 2H),7.78-7.46 (m, 3H), (trifluoromethyl)benzoyl] (M + 1)⁺; LC/MS 6.88 (d, J= 8.9 Hz, 1H). amino]pyridine-2- retention time carboxamide (Method C):(synthesized using 2,3- 2.41 minutes dichloro-4-fluoro-phenol fromPreparation 6) 343 4-[[6-[4- ESI-MS m/z ¹H NMR (400 MHz, DMSO-d₆) δ11.51 (difluoromethoxy)-3- calc. 533.08, (s, 1H), 8.57 (d, J = 5.5 Hz,1H), 8.34 (s, fluoro-2-methoxy- found 534.0 1H), 8.12 (s, 1H), 7.84 (d,J = 5.8 Hz, 2H), phenoxy]-2-fluoro-3- (M + 1)⁺; LC/MS 7.68 (s, 1H), 7.35(d, J = 73.0 Hz, 1H), (trifluoromethyl)benzoyl] retention time 7.14 (d,J = 46.5 Hz, 2H), 6.82 (d, J = 8.9 amino]pyridine-2- (Method C): Hz,1H), 3.83 (s, 3H). carboxamide 2.31 minutes (synthesized using 4-(difluoromethoxy)-3- fluoro-2-methoxy-phenol from Preparation 7) 3444-[[6-[2-ethyl-3-fluoro-4- ESI-MS m/z ¹H NMR (400 MHz, DMSO-d₆) δ 11.51(trifluoromethoxy)phenoxy]- calc. 549.09, (s, 1H), 8.56 (d, J = 5.4 Hz,1H), 8.30 (d, 2-fluoro-3- found 550.0 J = 2.2 Hz, 1H), 8.11 (d, J = 2.7Hz, 1H), (trifluoromethyl)benzoyl] (M + 1)⁺; LC/MS 7.90 (t, J = 8.6 Hz,1H), 7.80 (dd, J = 5.5, amino]pyridine-2- retention time 2.2 Hz, 1H),7.67 (d, J = 2.9 Hz, 1H), 7.53 carboxamide (Method C): (t, J = 8.8 Hz,1H), 7.12 (dd, J = 9.2, 1.8 (synthesized using 2- 2.73 minutes Hz, 1H),6.95 (d, J = 8.9 Hz, 1H), 2.62 (q, ethyl-3-fluoro-4- J = 7.5 Hz, 2H),1.01 (t, J = 7.5 Hz, 3H) (trifluoromethoxy)phenol from Preparation 8)345 4-[[6-[2-cyclopropyl-3- ESI-MS m/z ¹H NMR (400 MHz, DMSO-d₆) δ 11.47fluoro-4- calc. 561.09, (s, 1H), 8.56 (d, J = 5.4 Hz, 1H), 8.31 (s,(trifluoromethoxy)phenoxy]- found 562.0 1H), 8.11 (s, 1H), 7.88 (t, J =8.6 Hz, 1H), 2-fluoro-3- (M + 1)⁺; LC/MS 7.81 (dd, J = 5.5, 2.2 Hz, 1H),7.67 (d, J = (trifluoromethyl)benzoyl] retention time 2.9 Hz, 1H), 7.50(t, J = 8.7 Hz, 1H), amino]pyridine-2- (Method C): 7.09 (d, J = 9.0 Hz,1H), 6.91 (d, J = 8.9 carboxamide 2.75 minutes Hz, 1H), 1.81-1.69 (m,1H), 0.92-0.83 (synthesized using 2- (m, 2H), 0.83-0.74 (m, 2H).cyclopropyl-3-fluoro-4- (trifluoromethoxy)phenol from Preparation 9)

Example 34-[[6-(4-fluoro-2-methoxy-phenoxy)-2-methoxy-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(52)

Step 1:4-[[6-bromo-2-methoxy-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide

4-[[6-Bromo-2-fluoro-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(1.50 g, 3.693 mmol) was dissolved in MeOH (15 mL). Sodium methoxide(8.0 mL of 25% w/v, 37.02 mmol) was added and the reaction mixtureallowed to stir at 85° C. for 5 h. The cooled reaction mixture was takenup in ethyl acetate (75 mL) and washed with aqueous HCl (0.5 M, 1×75 mL)and brine (1×75 mL). The organic layer was dried over Na₂SO₄, filteredand concentrated under reduced pressure. The crude product waschromatographed on silica gel eluting with a ethyl acetate-hexanegradient to yield4-[[6-bromo-2-methoxy-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(620 mg, 40%) was obtained as a white foamy solid. ESI-MS m z calc.416.9936, found 420.0 (M+3)+; Retention time (Method C): 1.31 minutes.

Step 2:4-[[6-(4-fluoro-2-methoxy-phenoxy)-2-methoxy-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(52)

A vial was loaded with4-[[6-bromo-2-methoxy-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(20 mg, 0.04783 mmol) and 4-fluoro-2-methoxy-phenol (33.98 mg, 27.25 μL,0.2391 mmol). A solution of CsF (14.53 mg, 3.531 μL, 0.09566 mmol) inDMSO (0.25 mL) was added. Cs₂CO₃ (31.17 mg, 0.09566 mmol) was addedunder nitrogen gas. The vial was capped, and the reaction mixture wasstirred at 100° C. for 20 minutes. The product was purified by reversephase HPLC (gradient of 10-99% acetonitrile in water containing HCl as amodifier) to provide4-[[6-(4-fluoro-2-methoxy-phenoxy)-2-methoxy-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(3.4 mg, 14%). ESI-MS m/z calc. 479.11044, found 480.0 (M+1)⁺; Retentiontime (Method B): 1.71 minutes. ¹H NMR (400 MHz, DMSO-d₆) δ 11.38 (s,1H), 8.56 (s, 1H), 8.41 (s, 1H), 8.16 (s, 1H), 7.89 (s, 1H), 7.72 (s,1H), 7.67 (d, J=8.9 Hz, 1H), 7.25 (dd, J=8.9, 5.8 Hz, 1H), 7.16 (dd,J=10.7, 2.9 Hz, 1H), 6.86 (td, J=8.5, 2.9 Hz, 1H), 6.48 (d, J=8.8 Hz,1H), 3.90 (s, 3H), 3.77 (s, 3H) ppm.

The compounds set forth in Table 3 were prepared by methods analogous tothe preparation of compound 52 in Example 3.

TABLE 3 Additional Compounds Prepared By Methods Analogous to Example 3.Cmpd No. Compound Name LC/MS NMR (shifts in ppm) 53 4-[[6-(4- ESI-MS m/z¹H NMR (400 MHz, DMSO-d₆) δ isopropoxyphenoxy)-2- calc. 489.15115, 11.38(s, 1H), 8.55 (s, 1H), 8.37 (s, methoxy-3- found 490.05 1H), 8.14 (s,1H), 7.87 (s, 1H), 7.78- (trifluoromethyl)benzoyl]ami- (M + 1)+; 7.44(m, 2H), 7.12 (d, J = 9.0 Hz, 2H), no]pyridine-2-carboxamide Retentiontime 6.99 (d, J = 9.0 Hz, 2H), 6.61 (d, J = (Method B): 8.9 Hz, 1H),4.58 (p, J = 6.0 Hz, 1H), 1.85 minutes 3.91 (s, 3H), 1.26 (d, J = 6.0Hz, 6H). 54 4-[[6-(5-chloro-2-methoxy- ESI-MS m/z ¹H NMR (400 MHz,DMSO-d₆) δ phenoxy)-2-methoxy-3- calc. 495.08087, 11.34 (s, 1H), 8.56(s, 1H), 8.40 (s, (trifluoromethyl)benzoyl]ami- found 496.0 1H), 8.15(s, 1H), 7.86 (s, 1H), 7.70 (d, no]pyridine-2-carboxamide (M + 1)+; J =8.9 Hz, 2H), 7.40-7.32 (m, 2H), Retention time 7.24 (d, J = 9.6 Hz, 1H),6.57 (d, J = (Method B): 8.9 Hz, 1H), 3.91 (s, 3H), 3.76 (s, 3H). 1.78minutes 55 4-[[6-(3,4-difluorophenoxy)- ESI-MS m/z ¹H NMR (400 MHz,DMSO-d₆) δ 2-methoxy-3- calc. 467.09045, 11.39 (s, 1H), 8.56 (s, 1H),8.36 (s, (trifluoromethyl)benzoyl]ami- found 468.0 1H), 8.14 (s, 1H),7.84 (s, 1H), 7.76 (d, no]pyridine-2-carboxamide (M + 1)+; J = 8.9 Hz,1H), 7.70 (s, 1H), 7.55 (q, Retention time J = 9.5 Hz, 1H), 7.43 (ddd, J= 11.3, (Method B): 6.8, 2.9 Hz, 1H), 7.08 (d, J = 9.3 Hz, 1.74 minutes1H), 6.81 (d, J = 8.8 Hz, 1H), 3.92 (s, 3H). 56 4-[[6-(3-chloro-4-ESI-MS m/z ¹H NMR (400 MHz, DMSO-d₆) δ isopropoxy-phenoxy)-2- calc.523.1122, 11.34 (s, 1H), 8.55 (s, 1H), 8.36 (s, methoxy-3- found 523.961H), 8.13 (s, 1H), 7.84 (s, 1H), 7.73 (d, (trifluoromethyl)benzoyl]ami-(M + 1)+; J = 8.9 Hz, 1H), 7.69 (s, 1H), 7.36 (d,no]pyridine-2-carboxamide Retention time J = 2.9 Hz, 1H), 7.25 (d, J =9.1 Hz, (Method B): 1H), 7.15 (dd, J = 9.1, 2.9 Hz, 1H), 1.93 minutes6.74-6.66 (m, 1H), 4.80-4.51 (m, 1H), 3.91 (s, 3H), 1.28 (d, J = 6.1 Hz,6H). 57 4-[[6-(3-chloro-4-fluoro- ESI-MS m/z ¹H NMR (400 MHz, DMSO-d₆) δphenoxy)-2-methoxy-3- calc. 483.06088, 11.36 (s, 1H), 8.55 (s, 1H), 8.35(s, (trifluoromethyl)benzoyl]ami- found 484.0 1H), 8.13 (s, 1H), 7.83(s, 1H), 7.76 (d, no]pyridine-2-carboxamide (M + 1)+; J = 8.9 Hz, 1H),7.69 (s, 1H), 7.57- Retention time 7.48 (m, 2H), 7.25 (dt, J = 9.0, 3.5Hz, (Method B): 1H), 6.80 (d, J = 8.8 Hz, 1H), 3.92 (s, 1.81 minutes;3H). 58 4-[[6-(3,4-difluoro-2- ESI-MS m/z methoxy-phenoxy)-2- calc.497.101, methoxy-3- found 497.9 (trifluoromethyl)benzoyl]ami- (M + 1)+;no]pyridine-2-carboxamide Retention time (Method B): 1.77 minutes 594-[[6-(2-chloro-4-fluoro- ESI-MS m/z 1H NMR (400 MHz, DMSO-d6) δphenoxy)-2-methoxy-3- calc. 483.06088, 11.35 (s, 1H), 8.55 (d, J = 5.5Hz, 1H), (trifluoromethyl)benzoyl]ami- found 484.0 8.36 (s, 1H), 8.11(s, 1H), 7.85 (d, J = no]pyridine-2-carboxamide (M + 1)+; 5.3 Hz, 1H),7.73 (d, J = 9.0 Hz, 1H), Retention time 7.67 (dd, J = 8.3, 3.0 Hz, 2H),7.44 (Method B): (dd, J = 9.1, 5.3 Hz, 1H), 7.36 (ddd, J = 1.75 minutes9.1, 8.0, 3.0 Hz, 1H), 6.60 (d, J = 8.8 Hz, 1H), 3.92 (s, 3H). 604-[[6-[4- ESI-MS m/z (cyclohexoxy)phenoxy]-2- calc. 529.18243,methoxy-3- found 529.96 (trifluoromethyl)benzoyl]ami- (M + 1)+;no]pyridine-2-carboxamide Retention time (Method B): 2.05 minutes 614-[[6-(4-fluoro-3-methyl- ESI-MS m/z ¹H NMR (400 MHz, DMSO-d₆) δphenoxy)-2-methoxy-3- calc. 463.1155, 11.37 (s, 1H), 8.55 (s, 1H), 8.36(s, (trifluoromethyl)benzoyl]ami- found 464.05 1H), 8.13 (s, 1H), 7.85(s, 1H), 7.73 (d, no]pyridine-2-carboxamide (M + 1)+; J = 8.9 Hz, 1H),7.69 (s, 1H), 7.23 (t, J = Retention time 9.1 Hz, 1H), 7.16 (dd, J =6.3, 3.0 (Method B): Hz, 1H), 7.06 (dt, J = 8.4, 3.6 Hz, 1H), 1.8minutes 6.69 (d, J = 8.9 Hz, 1H), 3.92 (s, 3H), 2.23 (s, 3H). 624-[[6-(2,4-difluorophenoxy)- ESI-MS m/z ¹H NMR (400 MHz, DMSO-d₆) δ2-methoxy-3- calc. 467.09045, 11.42 (s, 1H), 8.56 (s, 1H), 8.38 (s,(trifluoromethyl)benzoyl]ami- found 468.0 1H), 8.14 (s, 1H), 7.87 (s,1H), 7.74 (d, no]pyridine-2-carboxamide (M + 1)+; J = 8.9 Hz, 1H), 7.69(s, 1H), 7.55 Retention time (ddd, J = 11.4, 8.9, 3.0 Hz, 1H), 7.45(Method B): (td, J = 9.1, 5.5 Hz, 1H), 7.21 (t, J = 1.71 minutes 8.6 Hz,1H), 6.70 (d, J = 8.8 Hz, 1H), 3.92 (s, 3H). 634-[[2-methoxy-6-phenoxy-3- ESI-MS m/z ¹H NMR (400 MHz, DMSO-d₆) δ(trifluoromethyl)benzoyl]ami- calc. 431.10928, 11.47 (s, 1H), 8.56 (s,1H), 8.39 (s, no]pyridine-2-carboxamide found 432.05 1H), 8.18 (s, 1H),7.87 (s, 1H), 7.74 (d, (M + 1)+; J = 8.9 Hz, 2H), 7.47 (t, J = 7.8 Hz,Retention time 2H), 7.27 (t, J = 7.4 Hz, 1H), 7.20 (d, (Method B): J =8.0 Hz, 2H), 6.68 (d, J = 8.8 Hz, 1.69 minutes 1H), 3.92 (s, 3H). 644-[[6-(4-fluoro-2-methyl- ESI-MS m/z ¹H NMR (400 MHz, DMSO-d₆) δphenoxy)-2-methoxy-3- calc. 463.1155, 11.38 (s, 1H), 8.56 (s, 1H), 8.38(s, (trifluoromethyl)benzoyl]ami- found 464.05 1H), 8.13 (s, 1H), 7.85(d, J = 5.1 Hz, no]pyridine-2-carboxamide (M + 1)+; 1H), 7.74-7.66 (m,2H), 7.25 (dd, J = Retention time 9.4, 3.0 Hz, 1H), 7.22-7.07 (m, 2H),(Method B): 6.51 (d, J = 8.8 Hz, 1H), 3.93 (s, 3H), 1.77 minutes 2.13(s, 3H). 65 4-[[6-[3-fluoro-4- ESI-MS m/z (trifluoromethoxy)phenoxy]-calc. 533.08215, 2-methoxy-3- found 533.86 (trifluoromethyl)benzoyl]ami-(M + 1)+; no]pyridine-2-carboxamide Retention time (Method B): 1.91minutes 66 4-[[6-[2-chloro-4- ESI-MS m/z ¹H NMR (400 MHz, DMSO-d₆) δ(trifluoromethoxy)phenoxy]- calc. 549.0526, 11.42 (s, 1H), 8.55 (s, 1H),8.36 (s, 2-methoxy-3- found 549.86 1H), 8.13 (s, 1H), 7.84 (s, 1H), 7.80(d, (trifluoromethyl)benzoyl]ami- (M + 1)+; J = 2.5 Hz, 1H), 7.77 (d, J= 8.9 Hz, no]pyridine-2-carboxamide Retention time 1H), 7.70 (s, 1H),7.55-7.45 (m, 2H), (Method B): 6.73 (d, J = 8.9 Hz, 1H), 3.93 (s, 3H).1.92 minutes 67 4-[[6-(3-fluoro-4- ESI-MS m/z isopropoxy-phenoxy)-2-calc. 507.14172, methoxy-3- found 508.05 (trifluoromethyl)benzoyl]ami-(M + 1)+; no]pyridine-2-carboxamide Retention time (Method B): 1.85minutes 68 4-[[6-[(4-fluoro-2,3- ESI-MS m/z dihydrobenzofuran-7- calc.491.11044, yl)oxy]-2-methoxy-3- found 492.0(trifluoromethyl)benzoyl]ami- (M + 1)+; no]pyridine-2-carboxamideRetention time (Method B): 1.73 minutes 69 4-[[6-(4-fluoro-3-methoxy-ESI-MS m/z ¹H NMR (400 MHz, DMSO-d₆) δ phenoxy)-2-methoxy-3- calc.479.11044, 11.41 (s, 1H), 8.56 (s, 1H), 8.39 (s,(trifluoromethyl)benzoyl]ami- found 479.95 1H), 8.15 (s, 1H), 7.86 (s,1H), 7.77- no]pyridine-2-carboxamide (M + 1)+; 7.68 (m, 2H), 7.31 (dd, J= 11.2, 8.8 Retention time Hz, 1H), 7.07 (dd, J = 7.4, 2.8 Hz, (MethodB): 1H), 6.80-6.74 (m, 1H), 6.72 (d, J = 1.72 minutes 8.9 Hz, 1H), 3.92(s, 3H), 3.82 (s, 3H). 70 4-[[2-methoxy-3- ESI-MS m/z(trifluoromethyl)-6-[[6- calc. 500.09192, (trifluoromethyl)-3- found501.0 pyridyl]oxy]benzoyl]amino] (M + 1)+; pyridine-2-carboxamideRetention time (Method B): 1.67 minutes 71 4-[[6-[(6-chloro-2-methoxy-ESI-MS m/z 3-pyridyl)oxy]-2-methoxy- calc. 496.07614, 3- found 496.95(trifluoromethyl)benzoyl]ami- (M + 1)+; no]pyridine-2-carboxamideRetention time (Method B): 1.73 minutes 258 4-[[6-(3- ESI-MS m/z ¹H NMR(400 MHz, DMSO-d₆) δ 11.34 cyclohexylphenoxy)-2- calc. 513.18756, (s,1H), 8.54 (d, J = 5.5 Hz, 1H), 8.36 methoxy-3- found 514.05 (s, 1H),8.11 (s, 1H), 7.90-7.78 (m, (trifluoromethyl)benzoyl]ami- (M + 1)+; 1H),7.74 (d, J = 8.9 Hz, 1H), 7.67 (s, no]pyridine-2-carboxamide Retentiontime 1H), 7.36 (t, J = 7.8 Hz, 1H), 7.12 (d, J = (Method B): 7.7 Hz,1H), 7.04-6.95 (m, 2H), 6.68 2.14 minutes (d, J = 8.9 Hz, 1H), 3.91 (s,3H), 2.48 (m, 1H, obscured by solvent), 1.85- 1.59 (m, 5H), 1.39-1.17(m, 5H).

Example 44-[[2-(2,3-difluoro-4-isopropoxy-phenoxy)-6-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(72)

Step 1:4-[[2-fluoro-6-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide

To a solution of 2-fluoro-6-(trifluoromethyl)benzoic acid (7.00 g, 33.64mmol) in DCM (70 mL) and DMF (100 μL, 1.291 mmol) at 0° C. was addedoxalyl chloride (23.5 mL, 269.4 mmol) drop-wise. The reaction mixturewas allowed to stir at RT for 1 hour. The reaction mixture wasconcentrated under reduced pressure and taken up in NMP (7 mL). Thisacid chloride solution was then added to a prepared solution of4-aminopyridine-2-carboxamide (4.61 g, 33.62 mmol) and DIEA (35. mL,200.9 mmol) in NMP (70 mL) and DMF (7 mL) at 0° C. The final reactionmixture was allowed to slowly warm to RT and stirred overnight. Thereaction mixture was diluted with ethyl acetate (100 mL) and washed withwater (1×100 mL) and brine (1×100 mL). The organic layer was dried overNa₂SO₄, filtered and concentrated under reduced pressure. The crudeproduct was chromatographed on a 120 gram silica gel column eluting witha 0-100% EtOAc/hexane gradient over 60 minutes.4-[[2-fluoro-6-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(881 mg, 8%) was obtained as an orange oil. ESI-MS m/z calc. 327.06308,found 328.2 (M+1)⁺; Retention time (Method B): 1.12 minutes. ¹H NMR (400MHz, DMSO-d6) δ 11.44 (s, 1H), 8.57 (d, J=5.4 Hz, 1H), 8.32 (d, J=2.1Hz, 1H), 8.12 (d, J=2.9 Hz, 1H), 7.87-7.74 (m, 4H), 7.72-7.62 (m, 1H)ppm.

Step 2:4-[[2-(2,3-difluoro-4-isopropoxy-phenoxy)-6-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(72)

A solution of4-[[2-fluoro-6-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide (40mg, 0.1222 mmol) in DMSO (0.5 mL) was added to2,3-difluoro-4-isopropoxy-phenol (68.98 mg, 0.3666 mmol). Finely groundK₂CO₃ (50.67 mg, 0.3666 mmol) was then added. The reaction mixture wasallowed to stir at 120° C. for 2 h. The mixture was purified by reversephase HPLC (gradient of 10-99% acetonitrile in water containing HCl as amodifier) to afford4-[[2-(2,3-difluoro-4-isopropoxy-phenoxy)-6-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(9.3 mg, 15%). ESI-MS m/z calc. 495.12173, found 496.31 (M+1)⁺;Retention time (Method B): 1.63 minutes. ¹H NMR (400 MHz, DMSO-d₆) δ11.40 (s, 1H), 8.55 (d, J=5.5 Hz, 1H), 8.33 (d, J=2.1 Hz, 1H), 8.13 (d,J=2.8 Hz, 1H), 7.82 (dd, J=5.5, 2.2 Hz, 1H), 7.72-7.59 (m, 3H), 7.28 (d,J=8.0 Hz, 1H), 7.10 (t, J=5.2 Hz, 2H), 4.65 (p, J=6.1 Hz, 1H), 1.30 (d,J=6.0 Hz, 6H) ppm.

The compounds set forth in Table 4 were prepared by methods analogous tothe preparation of compound 72 in Example 4.

TABLE 4 Additional Compounds Prepared By Methods Analogous to Example 4.Cmpd No. Compound Name LC/MS NMR (shifts in ppm) 73 4-[[2-[(6-chloro-2-ESI-MS m/z ¹H NMR (400 MHz, DMSO-d₆) δ 11.40 (s, methoxy-3-pyridyl)oxy]-calc. 466.06558, 1H), 8.54 (d, J = 5.5 Hz, 1H), 8.33 (d, J = 6- found467.25 2.1 Hz, 1H), 8.16 (s, 1H), 7.81 (dd, J = 5.5,(trifluoromethyl)benzoyl]ami- (M + 1)+; 2.2 Hz, 1H), 7.72 (s, 1H),7.69-7.58 (m, no]pyridine-2- Retention time 3H), 7.23 (d, J = 7.7 Hz,1H), 7.16 (d, J = carboxamide (Method B): 8.1 Hz, 1H), 3.84 (s, 3H).1.46 minutes (3 minute run) 74 4-[[2-(3-fluoro-4- ESI-MS m/z ¹H NMR (400MHz, DMSO-d₆) δ 11.31 (s, isopropoxy-phenoxy)-6- calc. 477.13116, 1H),8.53 (d, J = 5.5 Hz, 1H), 8.30 (d, J = (trifluoromethyl)benzoyl]ami-found 478.31 2.1 Hz, 1H), 8.12 (d, J = 2.8 Hz, 1H), 7.79 no]pyridine-2-(M + 1)+; (dd, J = 5.5, 2.2 Hz, 1H), 7.71-7.58 (m, carboxamide Retentiontime 3H), 7.26-7.20 (m, 2H), 7.14 (dd, J = 11.8, (Method B): 2.9 Hz,1H), 6.94 (dd, J = 8.9, 2.2 Hz, 1H), 1.59 minutes 4.56 (p, J = 6.0 Hz,1H), 1.27 (d, J = 6.0 Hz, (3 minute run) 6H). 75 4-[[2-(4-fluoro-2-ESI-MS m/z ¹H NMR (400 MHz, DMSO-d₆) δ 11.30 (s, methoxy-phenoxy)-6-calc. 449.09988, 1H), 8.53 (d, J = 5.5 Hz, 1H), 8.34 (d, J =(trifluoromethyl)benzoyl]ami- found 450.26 2.1 Hz, 1H), 8.11 (s, 1H),7.83 (dd, J = 5.4, no]pyridine-2- (M + 1)+; 2.2 Hz, 1H), 7.67 (s, 1H),7.60 (t, J = 8.1 carboxamide Retention time Hz, 1H), 7.53 (d, J = 7.9Hz, 1H), 7.21 (dd, (Method B): J = 8.9, 5.8 Hz, 1H), 7.15 (dd, J = 10.7,2.9 1.45 minutes Hz, 1H), 6.95 (d, J = 8.3 Hz, 1H), 6.84 (td, (3 minuterun) J = 8.4, 2.9 Hz, 1H), 3.77 (s, 3H). 76 4-[[2-[2-chloro-4- ESI-MSm/z (trifluoromethoxy)phenoxy]- calc. 519.04205, 6- found 520.26(trifluoromethyl)benzoyl]ami- (M + 1)+; no]pyridine-2- Retention timecarboxamide (Method B): 1.68 minutes. 77 4-[[2-(2,4- ESI-MS m/z ¹H NMR(400 MHz, DMSO-d₆) δ 11.43 (s, difluorophenoxy)-6- calc. 437.0799, 1H),8.55 (d, J = 5.5 Hz, 1H), 8.33 (d, J = (trifluoromethyl)benzoyl]ami-found 438.25 2.1 Hz, 1H), 8.16 (s, 1H), 7.83 (dd, J = 5.5,no]pyridine-2- (M + 1)+; 2.2 Hz, 1H), 7.71 (s, 1H), 7.69-7.62 (m,carboxamide Retention time 2H), 7.56-7.49 (m, 1H), 7.39 (td, J = 92,(Method B): 5.5 Hz, 1H), 7.24-7.15 (m, 2H). 1.43 minutes 784-[[2-[(4-fluoro-2,3- ESI-MS m/z ¹H NMR (400 MHz, DMSO-d₆) δ 11.33 (s,dihydrobenzofuran-7- calc. 461.09988, 1H), 8.54 (d, J = 5.5 Hz, 1H),8.33 (d, J = yl)oxy]-6- found 462.27 2.1 Hz, 1H), 8.12 (s, 1H), 7.82(dd, J = 5.6, (trifluoromethyl)benzoyl]ami- (M + 1)+; 22 Hz, 1H), 7.67(d, J = 2.9 Hz, 1H), 7.63 no]pyridine-2- Retention time (t, J = 8.2 Hz,1H), 7.56 (d, J = 7.9 Hz, 1H), carboxamide (Method B): 7.09 (d, J = 8.4Hz, 1H), 7.01 (dd, J = 9.0, 1.46 minutes 4.7 Hz, 1H), 6.75 (t, J = 8.5Hz, 1H), 4.64 (t, J = 8.7 Hz, 2H), 3.28 (t, J = 8.7 Hz, 2H). 794-[[2-(2-chloro-4-fluoro- ESI-MS m/z phenoxy)-6- calc. 453.05032,(trifluoromethyl)benzoyl]ami- found 454.22 no]pyridine-2- (M + 1)+;carboxamide Retention time (Method B): 1.5 minutes 804-[[2-(3-chloro-4-fluoro- ESI-MS m/z ¹H NMR (400 MHz, DMSO-d₆) δ 11.32(s, phenoxy)-6- calc. 453.05032, 1H), 8.53 (d, J = 5.5 Hz, 1H), 8.29 (d,J = (trifluoromethyl)benzoyl]ami- found 454.22 2.1 Hz, 1H), 8.12 (s,1H), 7.77 (dd, J = 5.5, no]pyridine-2- (M + 1)+; 2.2 Hz, 1H), 7.74-7.64(m, 3H), 7.53- carboxamide Retention time 7.44 (m, 2H), 7.33 (d, J = 7.8Hz, 1H), 7.20 (Method B): (dt, J = 9.1, 3.5 Hz, 1H). 1.56 minutes 814-[[2-(2-fluoro-4- ESI-MS m/z ¹H NMR (400 MHz, DMSO-d₆) δ 11.30 (s,isopropoxy-phenoxy)-6- calc. 477.13116, 1H), 8.54 (d, J = 5.5 Hz, 1H),8.37 (d, J = (trifluoromethyl)benzoyl]ami- found 478.31 2.1 Hz, 1H),8.14 (s, 1H), 7.84 (dd, J = 5.5, no]pyridine-2- (M + 1)+; 2.2 Hz, 1H),7.69 (s, 1H), 7.61 (t, J = 8.1 carboxamide Retention time Hz, 1H), 7.55(d, J = 7.8 Hz, 1H), 7.34- (Method B): 7.20 (m, 1H), 7.06 (d, J = 8.5Hz, 1H), 7.02- 1.58 minutes 6.89 (m, 2H), 4.64-4.49 (m, 1H), 1.12 (d, J= 6.0 Hz, 6H). 82 4-[[2-isobutoxy-6-[2- ESI-MS m/z ¹H NMR (400 MHz,DMSO-d₆) δ 11.32 (s, methoxy-4- calc. 587.1491, 1H), 8.55 (d, J = 5.5Hz, 1H), 8.36 (d, J = (trifluoromethoxy)phenoxy]- found 588.2 2.2 Hz,1H), 8.15-8.07 (m, 1H), 7.86 (dd, 3- (M + 1)+; J = 5.5, 2.2 Hz, 1H),7.74-7.64 (m, 2H), (trifluoromethyl)benzoyl]ami- Retention time7.35-7.28 (m, 1H), 7.24 (d, J = 2.7 Hz, no]pyridine-2- (Method B): 1H),7.09-6.97 (m, 1H), 6.54 (d, J = 8.9 carboxamide 2.05 minutes Hz, 1H),3.88 (d, J = 5.8 Hz, 2H), 3.79 (s, 3H), 2.08-1.74 (m, 1H), 0.85 (d, J =6.7 Hz, 6H).

Example 54-[[2-ethoxy-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(83)

Step 1:4-[(Z)-[(tert-Butylamino)-phenylsulfanyl-methylene]amino]pyridine-2-carboxamide

A flask equipped with a reflux condenser was charged with4-aminopyridine-2-carboxamide (1.12 g, 8.17 mmol),benzenesulfonylsulfanylbenzene (1.85 g, 7.39 mmol),2-isocyano-2-methyl-propane (3.0 mL, 27 mmol), copper (I) iodide (60 mg,0.32 mmol) and molecular sieves (2.2 g) in 2-methyltetrahydrofuran (10mL), and the mixture was heated at 75° C. for 24 hours. The reactionmixture was filtered through Celite and the cake was rinsed with ethylacetate. The filtrate was concentrated and dried under vacuum. Theresidue was purified by silica gel chromatography (0-60% ethylacetate/hexanes) to obtain4-[(Z)-[(tert-butylamino)-phenylsulfanyl-methylene]amino]pyridine-2-carboxamide(1.25 g, 51%). ESI-MS m/z calc. 328.14, found 329.2 (M+1)⁺; retentiontime (Method B): 1.07 minutes. ¹H NMR (400 MHz, DMSO-d6) δ 8.17 (dd,J=5.3, 0.6 Hz, 1H), 7.94 (d, J=3.0 Hz, 1H), 7.49 (s, 1H), 7.28 (dd,J=2.2, 0.6 Hz, 1H), 7.25-7.17 (m, 5H), 6.74 (dd, J=5.3, 2.2 Hz, 1H),6.66 (s, 1H), 1.35 (s, 9H) ppm.

Step 2:2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoicacid

A pressure flask was charged with6-bromo-2-fluoro-3-(trifluoromethyl)benzoic acid (5 g, 17.42 mmol),2-methoxy-4-(trifluoromethoxy)phenol (4.35 g, 20.90 mmol), cesiumcarbonate (11.35 g, 34.84 mmol) and toluene (50 mL). The mixture wasdegassed with nitrogen. After ca. 2 minutes, copper (I) iodide (663 mg,3.48 mmol) was added and the reaction was stirred at 100° C. for lhr.The reaction was diluted with 300 mL ethyl acetate and 200 mL of waterand the phases were separated. The aqueous layer was acidified to pH-3and extracted with ethyl acetate. The combined organic phases were driedover sodium sulfate, filtered and concentrated. The residue was purifiedby silica gel chromatography (ethyl acetate/hexane gradient, followed by9:1 dichloromethane:methanol) to afford2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoicacid (5.4503 g, 76%) as a pale green solid. ESI-MS m/z calc. 414.03,found 415.0 (M+1)⁺; retention time (Method B): 1.94 minutes. ¹H NMR (400MHz, DMSO-d6) δ 7.53 (t, J=8.4 Hz, 1H), 7.27-7.11 (m, 2H), 6.99 (ddd,J=8.8, 2.7, 1.3 Hz, 1H), 6.49 (d, J=8.8 Hz, 1H), 3.80 (s, 3H) ppm.

Step 3:4-[[2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide

A microwave vial charged with4-[(Z)-[(tert-butylamino)-phenylsulfanyl-methylene]amino]pyridine-2-carboxamide(75 mg, 0.29 mmol), tris[(Z)-1-methyl-3-oxo-but-1-enoxy]iron(approximately 2 mg, 0.0057 mmol) and2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoicacid (94 mg, 0.29 mmol) in isopropanol (2 mL) was heated at 83° C. for16 hours. The reaction mixture was cooled to room temperature and thesolvent evaporated. The crude material was taken up in dichloromethaneand washed with 1N HCl. The organic layer was dried over MgSO₄, filteredand concentrated. The residue was purified by silica gel chromatography(ethyl acetate/hexane gradient) to afford4-[[2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(80 mg, 64%). ESI-MS m/z calc. 533.08215, found 534.1 (M+1)⁺; retentiontime (Method B): 1.77 minutes. ¹H NMR (400 MHz, DMSO-d6) δ 11.45 (s,1H), 8.56 (d, J=5.5 Hz, 1H), 8.32 (d, J=2.2 Hz, 1H), 8.12 (d, J=2.7 Hz,1H), 7.86-7.77 (m, 2H), 7.72-7.64 (m, 1H), 7.38 (d, J=8.8 Hz, 1H), 7.27(d, J=2.8 Hz, 1H), 7.08-7.01 (m, 1H), 6.68 (d, J=8.9 Hz, 1H), 3.79 (s,3H) ppm.

Step 4:4-[[2-ethoxy-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(83)

To ethanol (12.95 mg, 16.41 μL, 0.2812 mmol) was added a solution of4-[[2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(30 mg, 0.05625 mmol) in DMSO (0.5 mL). Finely ground K₂CO₃ (31.10 mg,0.2250 mmol) was then added. The reaction mixture was capped and allowedto stir at 140° C. for 30 minutes. The reaction mixture was purified byHPLC to afford4-[[2-ethoxy-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(10.7 mg, 33%). ESI-MS m/z calc. 559.1178, found 560.3 (M+1)⁺; Retentiontime (Method B): 1.88 minutes. 1H NMR (400 MHz, DMSO-d₆) δ 11.32 (s,1H), 8.55 (d, J=5.5 Hz, 1H), 8.37 (d, J=2.1 Hz, 1H), 8.12 (s, 1H), 7.86(dd, J=5.5, 2.2 Hz, 1H), 7.75-7.61 (m, 2H), 7.32 (d, J=8.8 Hz, 1H), 7.24(d, J=2.7 Hz, 1H), 7.09-6.98 (m, 1H), 6.53 (d, J=8.9 Hz, 1H), 4.13 (q,J=7.0 Hz, 2H), 3.79 (s, 3H), 1.24 (t, J=7.0 Hz, 3H).

The compounds set forth in Table 5 were prepared by methods analogous tothe preparation of compound 83 in Example 5.

TABLE 5 Additional Compounds Prepared By Methods Analogous to Example 5.Cmpd No. Compound Name LC/MS NMR (shifts in ppm) 84 4-[[2- ESI-MS m/z ¹HNMR (400 MHz, DMSO-d₆) δ 11.11 (s, (cyclopropylmethoxy)- calc. 585.1335,1H), 8.36 (d, J = 5.5 Hz, 1H), 8.18 (d, J = 6-[2-methoxy-4- found 586.22.1 Hz, 1H), 7.93 (d, J = 2.8 Hz, 1H), 7.68 (trifluoromethoxy)phenoxy]-(M + 1)+; (dd, J = 5.6, 2.0 Hz, 1H), 7.54-7.45 (m, 3- Retention time2H), 7.12 (d, J = 8.9 Hz, 1H), 7.05 (d, J = (trifluoromethyl)benzo-(Method B): 2.7 Hz, 1H), 6.88-6.80 (m, 1H), 6.35 (d, J =yl]amino]pyridine-2- 1.96 minutes; 8.8 Hz, 1H), 3.72 (d, J = 7.1 Hz,2H), carboxamide 3.60 (s, 3H), 0.99-0.87 (m, 1H), 0.32- 0.23 (m, 2H),0.03-−0.05 (m, 2H). 85 4-[[2-(cyclopropoxy)-6- ESI-MS m/z ¹H NMR (400MHz, DMSO-d₆) δ 11.38 (s, [2-methoxy-4- calc. 571.1178, 1H), 8.54 (d, J= 5.5 Hz, 1H), 8.37 (d, J = (trifluoromethoxy)phenoxy]- found 572.2 2.1Hz, 1H), 8.12 (d, J = 2.8 Hz, 1H), 7.88 3- (M + 1)+; (dd, J = 5.5, 2.2Hz, 1H), 7.72-7.58 (m, (trifluoromethyl)benzo- Retention time 2H), 7.34(d, J = 8.8 Hz, 1H), 7.24 (d, J = yl]amino]pyridine-2- (Method B): 2.7Hz, 1H), 7.04 (d, J = 9.6 Hz, 1H), 6.47 carboxamide 1.89 minutes; (d, J= 8.9 Hz, 1H), 4.10 (tt, J = 5.9, 2.7 Hz, 1H), 3.78 (s, 3H), 0.76-0.69(m, 2H), 0.68- 0.56 (m, 2H). 86 4-[[2-[(2,2- ESI-MS m/z ¹H NMR (400 MHz,DMSO-d₆) δ 11.33 (s, difluorocyclopropyl)me- calc. 621.1146, 1H), 8.55(d, J = 5.5 Hz, 1H), 8.35 (d, J = thoxy]-6-[2-methoxy-4- found 622.2 2.1Hz, 1H), 8.12 (d, J = 2.8 Hz, 1H), 7.87 (trifluoromethoxy)phenoxy]- (M +1)+; (dd, J = 5.5, 2.2 Hz, 1H), 7.71 (d, J = 9.0 3- Retention time: Hz,1H), 7.68 (d, J = 2.7 Hz, 1H), 7.32 (d, J = (trifluoromethyl)benzo- 1.93minutes 8.8 Hz, 1H), 7.24 (d, J = 2.7 Hz, 1H), yl]amino]pyridine-2-(Method B); 7.04 (d, J = 9.0 Hz, 1H), 6.57 (d, J = 8.9 carboxamide Hz,1H), 4.28-4.18 (m, 1H), 4.08 (t, J = 9.6 Hz, 1H), 3.79 (s, 3H),2.17-1.98 (m, 1H), 1.75-1.58 (m, 1H), 1.42-1.28 (m, 1H). 874-[[2-(isobutylamino)-6- ESI-MS m/z 1H NMR (400 MHz, DMSO-d6) δ 11.18(s, [2-methoxy-4- calc. 586.1651, 1H), 8.52 (d, J = 5.5 Hz, 1H), 8.34(d, J = (trifluoromethoxy)phenoxy]- found 587.5 2.1 Hz, 1H), 8.08 (d, J= 2.9 Hz, 1H), 7.86 3- (M + 1)+; (dd, J = 5.5, 2.1 Hz, 1H), 7.63 (d, J =2.9 (trifluoromethyl)benzo- Retention time Hz, 1H), 7.48 (d, J = 8.9 Hz,1H), 7.27 (d, J = yl]amino]pyridine-2- (Method B): 8.8 Hz, 1H), 7.19 (d,J = 2.7 Hz, 1H), carboxamide 2.02 minutes 7.07-6.94 (m, 1H), 6.03 (d, J= 8.8 Hz, 1H), 5.01-4.86 (m, 1H), 3.77 (s, 3H), 3.00 (t, J = 6.4 Hz,2H), 1.87 (dh, J = 13.3, 6.8 Hz, 1H), 0.77 (d, J = 6.6 Hz, 6H).

Example 64-[[2-fluoro-4-(p-tolyl)-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(88)

Step 1:4-[[2-fluoro-4-(p-tolyl)-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(88)

A solution of4-(2-trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy)-4-bromo-6-fluorobenzamido)picolinamide,p-tolylboronic acid (approximately 15 mg, 0.110 mmol), K₂CO₃(approximately 15 mg, 0.110 mmol), Pd(dppf)₂Cl₂ (8 mg, 0.0098 mmol) indioxane (500 μL) and water (50 μL) was flushed with N₂ and heated at100° C. for 16 h. The reaction mixture was purified by reverse phaseHPLC (gradient of 10-99% acetonitrile in water containing HCl as amodifier) to give4-[[2-fluoro-4-(p-tolyl)-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(22.6 mg, 74%). ESI-MS m/z calc. 558.1606, found 559.4 (M+1)⁺; Retentiontime (Method B): 1.95 minutes. ¹H NMR (400 MHz, DMSO-d₆) δ 11.32 (s,1H), 8.54 (d, J=5.4 Hz, 1H), 8.32 (s, 1H), 8.13 (s, 1H), 7.84 (d, J=4.2Hz, 1H), 7.68 (s, 1H), 7.50 (d, J=7.8 Hz, 2H), 7.45 (d, J=10.4 Hz, 1H),7.31-7.24 (m, 3H), 7.17 (d, J=2.6 Hz, 1H), 7.02-6.92 (m, 1H), 6.82 (s,1H), 2.33 (s, 3H) ppm.

The compounds set forth in Table 6 were prepared by methods analogous tothe preparation of compound 88 in Example 6.

TABLE 6 Additional Compounds Prepared By Methods Analogous to Example 6.Cmpd No. Compound Name LC/MS NMR (shifts in ppm) 89 4-[[2-fluoro-4-(4-ESI-MS m/z ¹H NMR (400 MHz, DMSO-d₆) δ 11.35 (s, fluorophenyl)-6-[2-calc. 562.1355, 1H), 8.54 (d, J = 5.5 Hz, 1H), 8.33 (d, J =(trideuteriomethoxy)-4- found 563.3 2.1 Hz, 1H), 8.14 (s, 1H), 7.84 (dd,J = 5.7, (trifluoromethoxy)phe- (M + 1)+; 2.1 Hz, 1H), 7.73-7.64 (m,3H), 7.49 (d, J = noxy]benzoyl]amino]pyr- Retention time 9.9 Hz, 1H),7.34-7.25 (m, 3H), 7.17 idine-2-carboxamide (Method B): (d, J = 2.7 Hz,1H), 6.98 (dd, J = 8.8, 2.5 1.85 minutes Hz, 1H), 6.86 (s, 1H). (3minute run). 90 4-[[2-fluoro-4-(3- ESI-MS m/z ¹H NMR (400 MHz, DMSO-d₆)δ 11.52 (s, pyridyl)-6-[2- calc. 545.14014, 1H), 9.13-9.00 (m, 1H), 8.80(d, J = 5.1 (trideuteriomethoxy)-4- found 545.96 Hz, 1H), 8.56 (d, J =5.6 Hz, 1H), 8.47 (d, (trifluoromethoxy)phe- (M + 1)+; J = 8.1 Hz, 1H),8.35 (d, J = 2.1 Hz, 1H), noxy]benzoyl]amino]pyr- Retention time 8.19(s, 1H), 7.92-7.81 (m, 2H), 7.74 (s, idine-2-carboxamide (Method B):1H), 7.70 (dd, J = 10.0, 1.4 Hz, 1H), 7.30 1.41 minutes (d, J = 8.8 Hz,1H), 7.17 (d, J = 2.7 Hz, (3 minute run). 1H), 7.11 (s, 1H), 6.97 (d, J= 9.4 Hz, 1H). 91 4-[[2-fluoro-4-(4- ESI-MS m/z ¹H NMR (400 MHz,DMSO-d₆) δ 11.60 (s, pyridyl)-6-[2- calc. 545.14014, 1H), 8.93 (d, J =5.9 Hz, 2H), 8.56 (d, J = (trideuteriomethoxy)-4- found 546.01 5.5 Hz,1H), 8.35 (s, 1H), 8.26-8.18 (m, (trifluoromethoxy)phe- (M + 1)+; 3H),7.91-7.83 (m, 2H), 7.74 (s, 1H), noxy]benzoyl]amino]pyr- Retention time7.32 (d, J = 8.8 Hz, 1H), 7.22 (s, 1H), 7.18 idine-2-carboxamide (MethodB): (d, J = 2.7 Hz, 1H), 6.98 (d, J = 8.9 Hz, 1.38 minutes 1H). (3minute run). 92 4-[[2-fluoro-4-phenyl- ESI-MS m/z ¹H NMR (400 MHz,DMSO-d₆) δ 11.33 (s, 6-[2- calc. 544.1449, 1H), 8.54 (d, J = 5.3 Hz,1H), 8.32 (s, 1H), (trideuteriomethoxy)-4- found 545.3 8.12 (s, 1H),7.85 (d, J = 4.4 Hz, 1H), 7.67 (trifluoromethoxy)phe- (M + 1)+; (s, 1H),7.60 (d, J = 7.3 Hz, 2H), 7.52- noxy]benzoyl]amino]pyr- Retention time7.37 (m, 4H), 7.29 (d, J = 8.7 Hz, 1H), idine-2-carboxamide (Method B):7.18 (d, J = 2.6 Hz, 1H), 6.99 (d, J = 8.7 2.1 minutes Hz, 1H), 6.84 (s,1H). (3 minute run). 93 4-[[2-fluoro-6-[2- ESI-MS m/z ¹H NMR (400 MHz,DMSO-d₆) δ 11.37 (s, (trideuteriomethoxy)-4- calc. 612.1323, 1H), 8.55(d, J = 5.5 Hz, 1H), 8.33 (d, J = (trifluoromethoxy)phe- found 613.3 2.1Hz, 1H), 8.14 (d, J = 2.8 Hz, 1H), 7.88- noxy]-4-[4- (M + 1)+; 7.79 (m,5H), 7.69 (d, J = 2.8 Hz, 1H), (trifluoromethyl)phe- Retention time7.63-7.56 (m, 1H), 7.30 (d, J = 8.8 Hz, nyl]benzoyl]amino]pyridine-(Method B): 1H), 7.18 (d, J = 2.7 Hz, 1H), 6.99 (dd, J = 2-carboxamide2.0 minutes 9.0, 2.3 Hz, 1H), 6.94 (s, 1H). (3 minute run). 944-[[2-fluoro-6-[2- ESI-MS m/z ¹H NMR (400 MHz, DMSO-d₆) δ 11.36 (s,(trideuteriomethoxy)-4- calc. 612.1323, 1H), 8.54 (d, J = 5.5 Hz, 1H),8.32 (d, J = (trifluoromethoxy)phe- found 613.2 2.1 Hz, 1H), 8.13 (s,1H), 7.98-7.91 (m, noxy]-4-[3- (M + 1)+; 2H), 7.86-7.78 (m, 2H),7.75-7.61 (m, (trifluoromethyl)phe- Retention time 3H), 7.26 (d, J = 8.8Hz, 1H), 7.17 (d, J = nyl]benzoyl]amino]pyridine- (Method B): 2.6 Hz,1H), 7.04-6.93 (m, 2H). 2-carboxamide 1.97 minutes (3 minute run). 954-[[2-fluoro-6-[2- ESI-MS m/z ¹H NMR (400 MHz, DMSO-d₆) δ 11.42 (s,(trideuteriomethoxy)-4- calc. 612.1323, 1H), 8.56 (d, J = 5.4 Hz, 1H),8.37 (s, 1H), (trifluoromethoxy)phe- found 613.2 8.13 (s, 1H), 7.88 (d,J = 3.9 Hz, 1H), 7.83 noxy]-4-[2- (M + 1)+; (d, J = 7.8 Hz, 1H), 7.74(t, J = 7.6 Hz, (trifluoromethyl)phe- Retention time 1H), 7.70-7.60 (m,2H), 7.41 (d, J = 7.6 nyl]benzoyl]amino]pyridine- (Method B): Hz, 1H),7.30 (d, J = 8.8 Hz, 1H), 7.19- 2-carboxamide 1.94 minutes. 7.12 (m,2H), 6.98 (d, J = 8.2 Hz, 1H), 6.43 (s, 1H).

Example 74-[[4-cyclopentyl-2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(96)

Step 1: methyl4-bromo-2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoate

A mixture of Cs₂CO₃ (7.89 g, 24.22 mmol),2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenol (3.54 g, 16.77 mmol)and methyl 4-bromo-2,6-difluoro-benzoate (4.00 g, 15.93 mmol) in DMF (70mL) was stirred at ambient temperature for 20 h. The reaction wasdiluted with ethyl acetate and washed with water (×3) and brine. Theorganic layer was dried over anhydrous MgSO₄, filtered and concentratedunder reduced pressure. Silica gel chromatography (0-10% ethylacetate/hexane) provided methyl4-bromo-2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoate(6.091 g, 86%). ESI-MS m/z calc. 440.99142, found 443.1 (M+1)⁺;Retention time (Method A): 0.82 minutes. ¹H NMR (400 MHz, DMSO-d6) δ7.47 (dd, J=9.0, 1.7 Hz, 1H), 7.26 (d, J=8.8 Hz, 1H), 7.24 (d, J=2.8 Hz,1H), 7.00 (ddd, J=8.8, 2.7, 1.3 Hz, 1H), 6.73 (t, J=1.5 Hz, 1H), 3.83(s, 3H) ppm.

Step 2:4-bromo-2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoicacid

Methyl4-bromo-2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoate(6.09 g, 13.77 mmol) was dissolved in MeOH (60 mL) and treated with NaOH(40 mL of 1 M, 40.00 mmol). The reaction was heated to 40° C. andstirred for 2 h resulting in partial hydrolysis. Additional NaOH (23 mLof 6 M, 138.0 mmol) was added and the reaction stirred at 45° C. for 1hour. The reaction mixture was acidified with HCl (210 mL of 1 M, 210.0mmol) and extracted into ethyl acetate (×3). The combined organic layerswere dried over anhydrous MgSO₄, filtered and concentrated reducedpressure to provide4-bromo-2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoicacid (5.81 g, 99%) as a glassy oil. ESI-MS m/z calc. 426.97577, found429.0 (M+1)⁺; Retention time (Method A): 0.72 minutes. ¹H NMR (400 MHz,DMSO-d6) δ 13.78 (s, 1H), 7.42 (dd, J=8.9, 1.6 Hz, 1H), 7.25-7.20 (m,2H), 7.00 (ddd, J=8.8, 2.7, 1.3 Hz, 1H), 6.67 (t, J=1.4 Hz, 1H) ppm.

Step 3:4-[[4-bromo-2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide

To a solution of4-bromo-2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoicacid (4.0 g, 9.343 mmol), DMF (210 μL, 2.712 mmol) and DCM (48 mL) at 0°C. under N₂ (g) was added oxalyl dichloride (7 mL, 80.24 mmol). Thereaction was stirred at 0° C. for 10 minutes and then at RT foradditional 1 h. The mixture was concentrated under reduced pressure andredissolved in NMP (5 mL). This solution was added drop-wise to asuspension of 4-aminopyridine-2-carboxamide (1.28 g, 9.334 mmol), DMF(1.5 mL, 19.37 mmol), and DIEA (10 mL, 57.41 mmol) in NMP (10 mL) underN₂ atmosphere at 0° C. The resulting reaction mixture was slowly warmedto RT and stirred overnight. The mixture was partitioned between waterand ethyl acetate. The phases were separated and the aqueous layer wasextracted with ethyl acetate (1×). The combined organic layers werewashed with brine (2×), water (2×) then brine (1×). The organic layerwas dried over Na₂SO₄, filtered and concentrated to give a light brownfoam. The crude was purified by silica chromatography eluting with agradient of ethyl acetate-hexanes to give4-[[4-bromo-2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(1.26 g, 25%). ESI-MS m/z calc. 546.0241, found 549.0 (M+1)⁺; Retentiontime (Method B): 1.94 minutes. ¹H NMR (400 MHz, DMSO-d6) δ 11.30 (s,1H), 8.54 (d, J=5.4 Hz, 1H), 8.29 (d, J=2.1 Hz, 1H), 8.16-7.99 (m, 1H),7.82 (dd, J=5.6, 2.2 Hz, 1H), 7.65 (d, J=2.8 Hz, 1H), 7.52 (dd, J=8.6,1.5 Hz, 1H), 7.30 (d, J=8.8 Hz, 1H), 7.20 (d, J=2.7 Hz, 1H), 7.10-6.91(m, 1H), 6.75 (s, 1H) ppm.

Step 4:4-[[4-(cyclopenten-1-yl)-2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide

A solution of4-[[4-bromo-2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(25 mg, 0.04568 mmol), cyclopenten-1-ylboronic acid (13 mg, 0.1161mmol), K₂CO₃ (13 mg, 0.09406 mmol), ferrous;cyclopenta-1,4-dien-1-yl(diphenyl)phosphane; DCM; dichloropalladium (8mg, 0.009796 mmol) in dioxane (500 μL) and water (50 μL) was heated at100° C. for 16 h. The reaction mixture was filtered and purified byreverse phase HPLC (gradient of 10-99% acetonitrile in water containingHCl as a modifier) to obtain4-[[4-(cyclopenten-1-yl)-2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(18.2 mg, 74%). ESI-MS m/z calc. 534.1606, found 534.96 (M+1)⁺;Retention time (Method B): 2.01 minutes.

Step 5:4-[[4-cyclopentyl-2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(96)

A solution of4-[[4-(cyclopenten-1-yl)-2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(9 mg, 0.01680 mmol) in ethyl acetate (250 μL) and MeOH (250 μL) wasflushed with N2 (g). Palladium on Carbon (0.1788 mg, 0.001680 mmol) wasadded and the resulting mixture was purged with H₂ (balloon). Thereaction was stirred at RT under a hydrogen atmosphere for 16 h. Themixture was filtered and purified by reverse phase HPLC (gradient of10-99% acetonitrile in water containing HCl as a modifier) giving4-[[14-cyclopentyl-2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(6.6 mg, 73%). ESI-MS m/z cac. 536.1762, found 537.2 (M+1)⁺; Retentiontime (Method B): 1.94 minutes. ¹HNMR (400 MHz, DMSO-d₆) δ 11.25 (s, 1H),8.53 (d, J=5.5 Hz, 1H), 8.32 (d, J=2.1 Hz, 1H), 8.13 (s, 1H), 7.83 (dd,J=5.5, 2.2 Hz, 1H), 7.69 (s, 1H), 7.22 (d, J=8.7 Hz, 1H), 7.18 (d, J=2.7Hz, 1H), 7.03 (d, J=10.2 Hz, 1H), 6.99 (d, J=8.9 Hz, 1H), 6.46 (s, 1H),2.95 (p, J=9.0 Hz, 1H), 1.98-1.91 (m, 2H), 1.75-1.67 (min, 2H),1.649-1.56 (i, 2H), 1.462-1.41 ((, 2H) ppm.

The compounds set forth in Table 7 were prepared by methods analogous tothe preparation of compound 96.

TABLE 7 Additional Compounds Prepared By Methods Analogous to Example 7.Cmpd No. Compound Name LC/MS NMR (shifts in ppm) 97 4-[[4-cyclohexyl-2-ESI-MS m/z ¹H NMR (400 MHz, DMSO-d₆) δ 11.28 (s, fluoro-6-[2- calc.550.19183, 1H), 8.52 (d, J = 5.5 Hz, 1H), 8.33 (d, J = 2.1(trideuteriomethoxy)- found 551.3 Hz, 1H), 8.14 (s, 1H), 7.83 (dd, J =5.8, 2.1 4- (M + 1)+; Hz, 1H), 7.77-7.66 (m, 1H), 7.22 (d, J = 8.8(trifluoromethoxy)phe- Retention time Hz, 1H), 7.17 (d, J = 2.8 Hz, 1H),7.00 (t, J = noxy]benzoyl]ami- (Method B): 9.9 Hz, 2H), 6.44 (s, 1H),2.47 (m, 1H, no]pyridine-2- 2.04 minutes; obscured by DMSO), 1.85-1.60(m, 5H), carboxamide 1.44-1.10 (m, 5H). 98 4-[[4-(4,4- ESI-MS m/z ¹H NMR(400 MHz, DMSO-d₆) δ 11.38 (s, 1H), difluorocyclohexyl)- calc.586.17303, 8.54 (d, J = 5.6 Hz, 1H), 8.36 (d, J = 2.1 Hz, 2-fluoro-6-[2-found 587.3 1H), 8.21 (s, 1H), 7.94-7.82 (m, 1H), 7.76 (s,(trideuteriomethoxy)- (M + 1)+; 1H), 7.25 (d, J = 8.8 Hz, 1H), 7.19 (d,J = 2.7 4- Retention time Hz, 1H), 7.06 (d, J = 10.2 Hz, 1H), 7.04-6.92(trifluoromethoxy)phe- (Method B): (m, 1H), 6.46 (s, 1H), 2.82-2.63 (m,1H), 2.18- noxy]benzoyl]ami- 1.83 minutes 1.71 (m, 6H), 1.67-1.47 (m,2H). no]pyridine-2- carboxamide

Example 84-[[5-fluoro-2-[12-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(99)

Step 1: ethyl 2,5-difluoro-4-(trifluoromethyl)benzoate

To a solution of 2,5-difluoro-4-(trifluoromethyl)benzoic acid (5 g,22.11 mmol) in ethanol (50 mL) was added H₂SO₄ (1.5 mL, 28.14 mmol)dropwise over 5 minutes. The solution was heated at reflux for 48 h,then the reaction mixture was cooled to RT and concentrated underreduced pressure to provide ethyl2,5-difluoro-4-(trifluoromethyl)benzoate (4.57 g, 81%) as a clearcolorless liquid. ESI-MS m/z calc. 254.03662, Retention time (Method A):0.71 minutes (product does not ionize). ¹H NMR (400 MHz, DMSO-d6) δ 7.96(dd, J=10.1, 5.6 Hz, 2H), 4.37 (q, J=7.1 Hz, 2H), 1.33 (t, J=7.1 Hz, 3H)ppm.

Step 2:5-fluoro-2-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoicacid

A mixture of 2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenol (7.69 g,36.42 mmol), ethyl 2,5-difluoro-4-(trifluoromethyl)benzoate (8.41 g,33.09 mmol) and Cs₂CO₃ (16.17 g, 49.63 mmol) in acetonitrile (102.6 mL)was heated under reflux under N₂ overnight. The reaction mixture wasdiluted with water and acidified to ˜pH 2 with 6 N HCl. The mixture wasextracted with DCM (3×50 mL) and the combined organic layers dined overMgSO₄, filtered and concentrated. The residue was dissolved in MeOH (50mL) and treated with solid NaOH (2.647 g, 66.18 mmol) dissolved in 50 mLwater. The mixture was stirred for 20 minutes then acidified with anaqueous solution of HCl (9 mL of 12 M, 108.0 mmol). The aqueous mixturewas extracted with ethyl acetate, and the organic layer dried overMgSO₄, filtered and concentrated under reduced pressure. The residue waspurified by silica gel chromatography (0-3% MeOH/DCM with 0.2% AcOH) andproduct fractions were concentrated and the solid triturated 2× withhexanes to provide5-fluoro-2-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoicacid as a white solid. ESI-MS m/z calc. 417.05264, found 418.1 (M+1)⁺;Retention time (Method A): 0.74 minutes. ¹H NMR (500 MHz, DMSO-d6) δ13.69 (br s, 1H), 7.88 (d, J=10.4 Hz, 1H), 7.20 (d, J=2.7 Hz, 1H), 7.14(d, J=5.7 Hz, 1H), 7.07 (d, J=8.8 Hz, 1H), 6.95 (d, J=8.8 Hz, 1H) ppm.

Step 3:5-fluoro-2-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoylchloride

To a solution of5-fluoro-2-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoicacid (1.8 g, 4.314 mmol) and DMF (10 μL, 0.1291 mmol) in DCM (15 mL) at0° C. was added oxalyl chloride (565 μL, 6.477 mmol) drop-wise under N₂atmosphere. The ice bath was removed after 10 minutes and the reactionwas stirred at RT for 1.5 h. The solvent was evaporated under reducedpressure to afford5-fluoro-2-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoylchloride. The intermediate was used in the next step without furtherpurification.

Step 4:4-[[5-fluoro-2-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(99)

To5-fluoro-2-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoylchloride (60 mg, 0.1377 mmol) in NMP (0.3 mL) was added to a mixture of4-aminopyridine-2-carboxamide (28.32 mg, 0.2065 mmol) and DIEA (71.19mg, 95.94 μL, 0.5508 mmol) in NMP (0.3 mL). The reaction was stirred atRT for 2 h. The crudes were filtered and purified by reverse phase HPLC(gradient of 10-99% acetonitrile in water containing HCl as a modifier)to give4-[[5-fluoro-2-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(30.00 mg, 41%). ESI-MS m/z calc. 536.101, found 537.31 (M+1)⁺;Retention time (Method B): 1.83 minutes.

Example 95-[[5-fluoro-2-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(100)

To a solution of5-fluoro-2-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoylchloride (60 mg, 0.1377 mmol) in NMP (0.3 mL) was added a mixture of5-aminopyridine-2-carboxamide (28.32 mg, 0.2065 mmol) and DIEA (71.19mg, 95.94 μL, 0.5508 mmol) in NMP (0.3 mL). The reactions were stirredat RT for 2 h. The crude was filtered and purified by reverse phase HPLC(gradient of 10-99% acetonitrile in water containing HCl as a modifier)to give5-[[5-fluoro-2-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(27.80 mg, 37%). ESI-MS m/z calc. 536.101, found 536.96 (M+1)⁺;Retention time (Method B): 1.98 minutes. ¹H NMR (400 MHz, DMSO-d₆) δ11.07 (s, 1H), 8.84 (d, J=2.4 Hz, 1H), 8.22 (dd, J=8.6, 2.5 Hz, 1H),8.07-8.00 (m, 2H), 7.95 (d, J=10.1 Hz, 1H), 7.58 (s, 1H), 7.21 (dd,J=7.4, 5.3 Hz, 2H), 7.16 (d, J=2.7 Hz, 1H), 6.97 (dd, J=9.0, 2.3 Hz, 1H)ppm.

Example 105-[[2-fluoro-6-(4-fluoro-2-methyl-phenoxy)-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(101)

Step 1:2-fluoro-6-(4-fluoro-2-methyl-phenoxy)-3-(trifluoromethyl)benzoic acid

A solution of 6-bromo-2-fluoro-3-(trifluoromethyl)benzoic acid (24 g,83.62 mmol), 4-fluoro-2-methyl-phenol (11.33 g, 89.83 mmol), Cs₂CO₃(27.43 g, 84.19 mmol) in toluene (200 mL) was bubbled with N₂ for 10minutes then CuI (3.1 g, 16.28 mmol) was added. The flask was flushedwith N₂, capped, and heated at 100° C. with vigorous stirring for 3 h.The mixture was allowed to cool then diluted with ethyl acetate andwater (350 mL). The two layers were separated, the aqueous was layeracidified with HCl (375 mL of 1 M, 375.0 mmol) and extracted with ethylacetate (×3). The combined organic layer was washed with brine (×2),dried over Na₂SO₄, filtered through a plug of celite and concentratedundere reduced pressure. The crude product was titurated with hexane andfiltered to obtain2-fluoro-6-(4-fluoro-2-methyl-phenoxy)-3-(trifluoromethyl)benzoic acid(16 g, 58%) as a cream colored solid. ESI-MS m/z calc. 332.04718, found333.1 (M+1)⁺; Retention time (Method C): 2.39 minutes. ¹H NMR (500 MHz,DMSO-d6) δ 14.11 (s, 1H), 7.76 (t, J=8.6 Hz, 1H), 7.28 (dd, J=9.4, 3.0Hz, 1H), 7.22-7.11 (m, 2H), 6.58 (d, J=8.9 Hz, 1H), 2.13 (s, 3H) ppm.

Step 2:2-fluoro-6-(4-fluoro-2-methyl-phenoxy)-3-(trifluoromethyl)benzoylchloride

To 2-fluoro-6-(4-fluoro-2-methyl-phenoxy)-3-(trifluoromethyl)benzoicacid (600 mg, 1.806 mmol) and DMF (15 μL, 0.1937 mmol) in DCM (6 mL) at0° C. was added oxalyl chloride (237 μL, 2.717 mmol) dropwise under N₂atmosphere. The ice bath was removed after 10 minutes and the reactionwas stirred at RT for 1 h. The solvent was evaporated under reducedpressure to afford2-fluoro-6-(4-fluoro-2-methyl-phenoxy)-3-(trifluoromethyl)benzoylchloride. The intermediate was used in the next step without furtherpurification.

Step 3:5-[[2-fluoro-6-(4-fluoro-2-methyl-phenoxy)-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(101)

To 5-aminopyridine-2-carboxamide (28.15 mg, 0.2053 mmol) in NMP (400μL), and DIEA (66.34 mg, 89.41 μL, 0.5133 mmol) at 0° C. was added asolution of2-fluoro-6-(4-fluoro-2-methyl-phenoxy)-3-(trifluoromethyl)benzoylchloride (60 mg, 0.1711 mmol) in NMP (200 μL) slowly. The reaction wasstirred at RT for 16 h. The crude product was filtered and purified byreverse phase HPLC (gradient of 10-99% acetonitrile in water containingHCl as a modifier) yield5-[[2-fluoro-6-(4-fluoro-2-methyl-phenoxy)-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(39.5 mg, 51%). ESI-MS m/z calc. 451.09552, found 452.0 (M+1)⁺;Retention time (Method B): 1.81 minutes. ¹H NMR (400 MHz, DMSO-d6) δ11.40 (s, 1H), 8.86 (d, J=2.4 Hz, 1H), 8.31 (dd, J=8.7, 2.4 Hz, 1H),8.07 (d, J=8.6 Hz, 1H), 8.03 (s, 1H), 7.83 (t, J=8.7 Hz, 1H), 7.58 (s,1H), 7.24 (ddd, J=17.5, 9.1, 4.0 Hz, 2H), 7.15 (td, J=8.5, 3.0 Hz, 1H),6.65 (d, J=8.9 Hz, 1H), 2.14 (s, 3H) ppm.

Example 114-[[2-fluoro-6-(4-fluoro-2-methyl-phenoxy)-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(102)

To 4-aminopyridine-2-carboxamide (28.15 mg, 0.2053 mmol) in NMP (400 μL)and DIEA (66.34 mg, 89.41 μL, 0.5133 mmol) at 0° C. was added a solutionof 2-fluoro-6-(4-fluoro-2-methyl-phenoxy)-3-(trifluoromethyl)benzoylchloride (60 mg, 0.1711 mmol) in NMP (200 μL) slowly. The reaction wasstirred at RT for 16 h. The crude product was filtered and purified byreverse phase HPLC (gradient of 10-99% acetonitrile in water containingHCl as a modifier) to yield4-[[2-fluoro-6-(4-fluoro-2-methyl-phenoxy)-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(28.9 mg, 37%). ESI-MS m/z calc. 451.09552, found 452.0 (M+1)⁺;Retention time (Method B): 1.8 minutes. ¹H NMR (400 MHz, DMSO-d6) δ11.48 (s, 1H), 8.57 (d, J=5.4 Hz, 1H), 8.33 (d, J=2.1 Hz, 1H), 8.11 (d,J=2.8 Hz, 1H), 7.94-7.80 (m, 2H), 7.67 (s, 1H), 7.36-7.07 (m, 3H), 6.64(d, J=8.9 Hz, 1H), 2.13 (d, J=5.0 Hz, 3H) ppm.

Example 124-[[2-fluoro-6-(4-fluoro-2-methoxy-phenoxy)-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(103)

Step 1:2-fluoro-6-(4-fluoro-2-methoxy-phenoxy)-3-(trifluoromethyl)benzoic acid

A solution of 6-bromo-2-fluoro-3-(trifluoromethyl)benzoic acid (20 g,69.68 mmol), 4-fluoro-2-methoxy-phenol (10 g, 70.36 mmol), Cs₂CO₃ (25 g,76.73 mmol) in toluene (250 mL) was bubbled with N₂ for 15 minutes thenCuI (2.8 g, 14.70 mmol) added. The flask was flushed with N₂, andstirred at RT for 16 h, then heated to 100° C. with stirring for 5 h.The mixture was allowed to cool, then diluted with ethyl acetate andwater. The water layer was acidified with HCl (142 mL of 1 M, 142.0mmol) and the product extracted into ethyl acetate. The organic layerwas washed with brine, dried over Na₂SO₄, filtered and concentrated. Theresulting gummy residue was dissolved in ethyl acetate and filteredthrough a pad of celite and the filtrate was concentrated. The brownresidue was dissolved in DCM/ethyl acetate and purified by silicachromatography in a 330 g silica column with a shallow (0-10%) gradientsystem of DCM/MeOH (0.5% AcOH). The resultant material was dissolved ina minimum amount of DCM and hexanes and allowed to stand overnight. Theresultant precipitate was filtered, washed with hexane and dried undervacuum to give2-fluoro-6-(4-fluoro-2-methoxy-phenoxy)-3-(trifluoromethyl)benzoic acid(9.8 g, 31%) as a light brown solid. ESI-MS m/z calc. 348.0421, found349.1 (M+1)⁺; Retention time (Method A): 0.58 minutes.

Step 2:2-fluoro-6-(4-fluoro-2-methoxy-phenoxy)-3-(trifluoromethyl)benzoylchloride

To a solution of2-fluoro-6-(4-fluoro-2-methoxy-phenoxy)-3-(trifluoromethyl)benzoic acid(700 mg, 1.568 mmol) and DMF (34 μL, 0.4391 mmol) in DCM (6.5 mL) at 0°C. was added oxalyl chloride (1.1 mL, 12.61 mmol) dropwise under N₂atmosphere. The ice bath was removed after 10 minutes and the reactionwas stirred at RT for 50 minutes. The mixture was concentrated todryness under reduced pressure to afford the crude2-fluoro-6-(4-fluoro-2-methoxy-phenoxy)-3-(trifluoromethyl)benzoylchloride. The intermediate was immediately used in the next step withoutpurification.

Step 3:4-[[2-fluoro-6-(4-fluoro-2-methoxy-phenoxy)-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(103)

To a solution of 4-aminopyridine-2-carboxamide (13.46 mg, 0.09818 mmol),DMF (5.981 mg, 6.336 μL, 0.08182 mmol) and NMP (200 μL) was added DIEA(31.73 mg, 42.76 μL, 0.2455 mmol) under N₂ atmosphere and the resultingclear solution was cooled to 0° C. A solution of2-fluoro-6-(4-fluoro-2-methoxy-phenoxy)-3-(trifluoromethyl)benzoylchloride (30 mg, 0.08182 mmol) in NMP (200 μL) was added and thereaction was stirred at RT for 16 h. The mixture was filtered andpurified by reverse phase HPLC (gradient of 10-99% acetonitrile in watercontaining HCl as a modifier) giving the desired product4-[[2-fluoro-6-(4-fluoro-2-methoxy-phenoxy)-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(18.4 mg, 48%). ESI-MS m/z calc. 467.09045, found 468.0 (M+1)⁺;Retention time (Method B): 1.73 minutes. ¹H NMR (400 MHz, DMSO-d₆) δ11.47 (s, 1H), 8.57 (d, J=5.5 Hz, 1H), 8.34 (d, J=2.1 Hz, 1H), 8.14 (s,1H), 7.86 (dd, J=5.5, 2.2 Hz, 1H), 7.80 (t, J=8.7 Hz, 1H), 7.76-7.65 (m,1H), 7.34-7.08 (m, 2H), 6.88 (td, J=8.5, 2.8 Hz, 1H), 6.59 (dd, J=30.6,8.9 Hz, 1H), 3.76 (d, J=2.2 Hz, 3H) ppm.

The compounds set forth in Table 8 were prepared by methods analogous tothe preparation of compound 103 in example 12.

TABLE 8 Additional Compounds Prepared By Methods Analogous to Example12. Cmpd No. Compound Name LC/MS NMR (shifts in ppm) 1045-[[2-fluoro-6-(4-fluoro-2- ESI-MS m/z methoxy-phenoxy)-3- calc.467.09045, (trifluoromethyl)benzoyl]ami- found 468.0no]pyridine-2-carboxamide (M + 1)+; Retention time (Method B): 1.72minutes

Example 134-[[2-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(105)

Step 1:2-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)benzaldehyde

To a stirring solution of 2-fluoro-5-(trifluoromethyl)benzaldehyde (5.02g, 26.13 mmol) in DMF (50 mL) in an ice bath was added Cs₂CO₃ (10.68 g,32.78 mmol) and 2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenol (6.50g, 30.78 mmol). The reaction mixture was warmed to RT then stirred for16 h. The reaction mixture was partitioned between ethyl acetate andwater. The organic layer was washed with water, 50% saturated aqueousNaHCO₃ and brine, then dried over MgSO₄, filtered and concentrated invacuo. Silica gel chromatography (220 g silica, 0-30% ethylacetate/hexane) provided2-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)benzaldehyde(8.84 g, 88%). ESI-MS m/z calc. 383.06717, found 384.0 (M+1)⁺; Retentiontime (Method A): 0.81 minutes. ¹H NMR (500 MHz, DMSO-d6) δ 10.50 (s,1H), 8.06 (s, 1H), 7.92 (dd, J=8.9, 2.4 Hz, 1H), 7.44 (d, J=8.7 Hz, 1H),7.29 (d, J=2.5 Hz, 1H), 7.07 (d, J=8.7 Hz, 1H), 6.88 (d, J=8.8 Hz, 1H)ppm.

Step 2:2-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)benzoicacid

A mixture of2-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)benzaldehyde(8.84 g, 23.07 mmol) and NaH₂PO₄ (2.92 g, 24.34 mmol) in tert-butylalcohol (80 mL)/water (40 mL)/acetonitrile (40 mL) was cooled in an icebath then 2-methy-2-butene (11 mL, 103.8 mmol) was added. Sodiumchlorite (3.12 g, 27.60 mmol) was then added portion wise over 10minutes. The mixture was allowed to warm to RT then stirred for 16 h.The reaction mixture was acidified to pH 1-2 using aqueous HCl (8 mL of12 M, 96.00 mmol), and partitioned with ethyl acetate. The organic layerwas separated, dried over MgSO₄ and concentrated in vacuo to afford2-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)benzoicacid (7.55 g, 82%) as a white solid. ESI-MS m/z calc. 399.06207, found400.1 (M+1)⁺; Retention time (Method A): 0.72 minutes. ¹H NMR (400 MHz,DMSO-d6) δ 13.38 (s, 1H), 8.07 (d, J=2.4 Hz, 1H), 7.81 (dd, J=8.9, 2.4Hz, 1H), 7.28-7.20 (m, 2H), 7.01 (dd, J=8.9, 1.7 Hz, 1H), 6.83 (d, J=8.7Hz, 1H) ppm.

Step 3:2-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)benzoylchloride

To2-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)benzoicacid (1.5 g, 3.757 mmol) and DMF (10 μL, 0.1291 mmol) in DCM (12 mL) at0° C. was added oxalyl chloride (492 μL, 5.640 mmol) dropwise under N₂atmosphere. The ice bath was removed after 10 minutes and the reactionwas stirred at RT for 1.5 h. The solvent was evaporated under reducedpressure to afford2-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)benzoylchloride. The intermediate was used in the next step without furtherpurification.

Step 4:4-[[2-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(105)

2-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)benzoylchloride (50 mg, 0.1197 mmol) in NMP (0.3 mL) was added to a mixture of4-aminopyridine-2-carboxamide (16.42 mg, 0.1197 mmol) and DIEA (15.47mg, 20.85 μL, 0.1197 mmol) in NMP (0.3 mL), and the reaction was stirredat RT for 2 h. The crude was filtered and purified by reverse phase HPLC(gradient of 10-99% acetonitrile in water containing HCl as a modifier)to give4-[[2-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(34.70 mg, 56%). ESI-MS m/z calc. 518.1104, found 519.32 (M+1)⁺;Retention time (Method B): 1.84 minutes.

The compounds set forth in Table 9 were prepared by methods analogous tothe preparation of compound 105 in Example 13.

TABLE 9 Additional Compounds Prepared By Methods Analogous to Example13. Cmpd No. Compound Name LC/MS NMR (shifts in ppm) 106 5-[[2-[2-ESI-MS m/z 1H NMR (400 MHz, DMSO-d6) δ (trideuteriomethoxy)-4- calc.518.1104, 10.95 (s, 1H), 8.91 (s, 1H), 8.29 (d, J =(trifluoromethoxy)phenoxy]- found 519.32 10.8 Hz, 1H), 8.04 (s, 3H),7.81 (d, 5- (M + 1)+; J = 10.9 Hz, 1H), 7.55 (s, 1H), 7.39(trifluoromethyl)benzoyl]ami- Retention time (d, J = 8.8 Hz, 1H), 7.24(s, 1H), no]pyridine-2-carboxamide (Method B): 7.05 (d, J = 8.8 Hz, 1H),6.89 (d, J = 1.83 minutes 8.7 Hz, 1H).

Example 144-[[2-(3-chloro-4-fluoro-phenoxy)-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(107)

Step 1:4-[[2-bromo-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide

To a solution of 2-bromo-4-(trifluoromethyl)benzoic acid (1 g, 3.7173mmol) and 4-aminopyridine-2-carboxamide (510 mg, 3.7189 mmol) inpyridine (30 mL) was added POCl₃ (575.75 mg, 0.350 mL, 3.7549 mmol) at−25° C. and stirred for 30 minutes at this temperature. The reaction wasquenched by addition of water (20 mL) then extracted with ethyl acetate(100×2). The organics were washed with water (3×30 mL), brine, driedover MgSO₄, filtered then concentrated in vacuo to provide a4-[[2-bromo-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide.ESI-MS m/z calc. 386.983, found 388.6 (M+1)⁺; Retention time (Method H):4.18 minutes. Used directly in the next step without furtherpurification.

Step 2:4-[[2-(3-chloro-4-fluoro-phenoxy)-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(107)

To a mixture of4-[[2-bromo-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide (25mg, 0.06441 mmol), 3-chloro-4-fluoro-phenol (9.439 mg, 0.06441 mmol),Cs₂CO₃ (41.97 mg, 0.1288 mmol), CuI (7.361 mg, 0.03865 mmol), CsF (48.91mg, 11.89 μL, 0.3220 mmol), and DMF (500.0 μL), was stirred at 150° C.for 1 h. The reaction was diluted with DMSO (500 uL), filtered, andpurified by reverse phase HPLC (gradient of 10-99% acetonitrile in watercontaining HCl as a modifier) to give4-[[2-(3-chloro-4-fluoro-phenoxy)-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(11.9 mg, 39%) as a white solid. ESI-MS m/z calc. 453.05032, found 453.9(M+1)⁺; Retention time (Method B): 1.68 minutes. ¹H NMR (400 MHz,DMSO-d6) δ 11.11 (s, 1H), 8.53 (d, J=5.5 Hz, 1H), 8.30 (d, J=2.1 Hz,1H), 8.10 (d, J=2.7 Hz, 1H), 8.02-7.88 (m, 1H), 7.82 (dd, J=5.5, 2.2 Hz,1H), 7.74-7.68 (m, 1H), 7.66 (d, J=2.7 Hz, 1H), 7.52-7.40 (m, 2H), 7.36(d, J=1.6 Hz, 1H), 7.17 (ddd, J=9.1, 3.9, 3.0 Hz, 1H) ppm.

The compounds set forth in Table 10 were prepared by methods analogousto the preparation of compound 107 in Example 13

TABLE 10 Additional Compounds Prepared By Methods Analogous to Example13. Cmpd No. Compound Name LC/MS NMR (shifts in ppm) 1084-[[2-(3-chloro-4-isopropoxy- ESI-MS m/z phenoxy)-4- calc. 493.10162,(trifluoromethyl)benzoyl]ami- found 494.29 no]pyridine-2-carboxamide(M + 1)+; Retention time (Method B): 1.66 minutes 109 4-[[2-[4- ESI-MSm/z ¹H NMR (400 MHz, DMSO-d₆) δ (cyclohexoxy)phenoxy]-4- calc. 499.1719,11.09 (s, 1H), 8.53 (d, J = 5.5 Hz, (trifluoromethyl)benzoyl]ami- found500.39 1H), 8.32 (d, J = 2.1 Hz, 1H), no]pyridine-2-carboxamide (M +1)+; 8.10 (d, J = 2.9 Hz, 1H), 7.90- Retention time 7.82 (m, 2H), 7.66(d, J = 2.9 Hz, (Method B): 1H), 7.62-7.56 (m, 1H), 7.15- 1.97 minutes7.04 (m, 3H), 7.04-6.95 (m, 2H), 4.28 (dt, J = 8.4, 4.6 Hz, 1H), 1.90(d, J = 10.9 Hz, 2H), 1.71 (s, 2H), 1.53 (d, J = 12.1 Hz, 1H), 1.42-1.23(m, 5H). 110 4-[[2-(3-cyclohexylphenoxy)- ESI-MS m/z ¹H NMR (400 MHz,DMSO-d₆) δ 4- calc. 483.17697, 11.09 (s, 1H), 8.51 (d, J = 5.5 Hz,(trifluoromethyl)benzoyl]ami- found 484.39 1H), 8.29 (d, J = 2.1 Hz,1H), 8.09 no]pyridine-2-carboxamide (M + 1)+; (s, 1H), 7.90 (d, J = 7.9Hz, 1H), Retention time 7.82 (dd, J = 5.7, 2.2 Hz, 1H), 7.66 (Method B):(d, J = 7.7 Hz, 2H), 7.31 (t, J = 7.9 2.03 minutes Hz, 1H), 7.24 (s,1H), 7.04 (d, J = 7.7 Hz, 1H), 6.97 (d, J = 2.5 Hz, 1H), 6.88 (dd, J =8.2, 2.4 Hz, 1H), 2.49-2.39 (m, 1H), 1.77-1.61 (m, 5H), 1.37-1.13 (m,5H). 111 4-[[2-(2,4-difluorophenoxy)-4- ESI-MS m/z ¹H NMR (400 MHz,DMSO-d₆) δ (trifluoromethyl)benzoyl]ami- calc. 437.0799, 11.27 (s, 1H),8.71 (s, 1H), 8.29- no]pyridine-2-carboxamide found 436.3 8.13 (m, 3H),7.96 (d, J = 1.5 Hz, (M + 1)+; 1H), 7.75 (s, 1H), 7.44 (s, 1H),Retention time 7.29 (s, 1H), 6.95 (s, 1H), 6.81 (Method B): (td, J =8.6, 2.9 Hz, 1H), 6.66 (s, 1.27 minutes 1H). 1124-[[2-[2-(1,1-difluoroethyl)-4- ESI-MS m/z ¹H NMR (400 MHz, DMSO-d6) δfluoro-phenoxy]-4- calc. 483.10175, 11.12 (s, 1H), 8.53 (d, J = 5.4 Hz,(trifluoromethyl)benzoyl]ami- found 484.0 1H), 8.32 (s, 1H), 8.08 (s,1H), no]pyridine-2-carboxamide (M + 1)+; 7.94 (d, J = 8.0 Hz, 1H), 7.83(s, Retention time 1H), 7.71-7.63 (m, 2H), 7.44 (d, (Method B): J = 8.6Hz, 2H), 7.15 (s, 1H), 2.02- 1.71 minutes 1.90 (m, 2H). 1134-[[2-(4-fluoro-2-methyl- ESI-MS m/z ¹H NMR (500 MHz, DMSO-d6) δphenoxy)-4- calc. 433.10495, 11.12 (d, J = 2.7 Hz, 1H), 8.54 (d,(trifluoromethyl)benzoyl]ami- found 433.9 J = 5.5 Hz, 1H), 8.33 (d, J =2.2 no]pyridine-2-carboxamide (M + 1)+; Hz, 1H), 8.10 (d, J = 2.9 Hz,1H), Retention time 7.91 (d, J = 7.9 Hz, 1H), 7.85 (dd, (Method B): J =5.4, 2.2 Hz, 1H), 7.70-7.59 1.68 minutes (m, 2H), 7.24-7.18 (m, 1H),7.15- 7.07 (m, 2H), 6.99 (d, J = 1.7 Hz, 1H), 2.16 (s, 3H)

Example 154-[[2,2-difluoro-5-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-1,3-benzodioxole-4-carbonyl]amino]pyridine-2-carboxamide(114)

Step 1: 5-bromo-2,2-difluoro-1,3-benzodioxole-4-carboxylic acid

To a solution of 2, 2, 6, 6-tetramethylpiperidine (12.03 g, 14.5 mL,85.20 mmol) in THF (170 mL) was added n-butyl lithium in hexanes (33.5mL of 2.5 M, 83.75 mmol) at 0° C. and the mixture was stirred at thistemperature for 30 minutes, then cooled to −78° C. and stirred for 30minutes. To a −78° C. solution of 5-bromo-2,2-difluoro-1,3-benzodioxole(20 g, 84.389 mmol) in THF (30 mL) was added the previously preparedLiTMP via cannula at −78° C. over 25 minutes. The reaction was stirredat this temperature for 25 minutes, then the reaction mixture wastransferred, using the same cannula, into a wide mouthed flaskcontaining crushed CO₂ (200.00 g, 4.54 mol) and stirred gently. Then,the reaction was slowly warmed to room temperature over 12 h. Thereaction was diluted with NaOH (1M, 950 mL), washed with Et₂O (3×650mL), and the aqueous phase was acidified at 0° C. with HCl (6 M, untilpH=1, gas evolved) and extracted with Et₂O (3×750 mL), dried over MgSO₄,then filtered and concentrated under reduced pressure to provide pure5-bromo-2,2-difluoro-1,3-benzodioxole-4-carboxylic acid (19.27 g, 81%).¹H NMR (500 MHz, DMSO-d6) δ 7.58 (d, J=9 Hz, 1H), 7.51 (d, J=9 Hz, 1H)ppm. ESI-MS m/z calc. 279.9183, found 281.1 (M+1)⁺; Retention time: 1.87minutes. LCMS Method: Water Cortex 2.7u C18 (3.0 mm×50 mm), Temp: 55c;Flow: 1.2 mL/min; MP: 100% water with 0.1% trifluoroacetic (TFA) acidthen 100% acetonitrile with 0.10% TFA acid, grad:5% to 100% B over 4min, with stay at 100% B for 0.5 min, equilibration to 5% B over 1.5min.

Step 2:2,2-difluoro-5-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-1,3-benzodioxole-4-carboxylicacid

A solution of 5-bromo-2,2-difluoro-1,3-benzodioxole-4-carboxylic acid (2g, 7.117 mmol), 2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenol (1.52g, 7.199 mmol), Cs₂CO₃ (2.38 g, 7.305 mmol) in toluene (15 mL) wasbubbled with N₂ for 10 minutes, then CuI (286 mg, 1.502 mmol) added. Theflask was flushed with N₂, capped, and heated at 100° C. with vigorousstirring for 7 h. The mixture was allowed to cool then diluted withethyl acetate and 50 mL water. The two layers were separated. Theorganic layer contained some product. The water layer was acidified withHCl (30 mL of 1 M, 30.00 mmol) and the product was extracted into ethylacetate (×3). The combined organic layer was washed with brine (×2),dried over Na₂SO₄, filtered through a plug of celite and concentrated.The crude product was purified on silica gel (gradient of 0-50% ethylacetate in hexane). The product was titurated with hexane to yield2,2-difluoro-5-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-1,3-benzodioxole-4-carboxylicacid (1.1206 g, 38%) as a light brown solid. ESI-MS m/z calc. 411.0457,found 412.2 (M+1)⁺; Retention time (Method C): 2.48 minutes (5 minutesrun).

Step 3:2,2-difluoro-5-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-1,3-benzodioxole-4-carbonylchloride

To a slurry of2,2-difluoro-5-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-1,3-benzodioxole-4-carboxylicacid (300 mg, 0.7295 mmol) and DMF (15 μL, 0.1937 mmol) in DCM (2.5 mL)at 0° C. was added oxalyl chloride (192 μL, 2.201 mmol) dropwise underN₂ atmosphere. The ice bath was removed after 10 minutes and thereaction was stirred at RT for 1.5 h. The solvent was evaporated underreduced pressure to afford2,2-difluoro-5-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-1,3-benzodioxole-4-carbonylchloride. The intermediate was used in the next step without furtherpurification. ESI-MS m/z calc. 478.12427, found 479.2 (M+1)⁺; Retentiontime (Method A): 0.77 minutes.

Step 4:4-[[2,2-difluoro-5-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-1,3-benzodioxole-4-carbonyl]amino]pyridine-2-carboxamide(114)

To 4-aminopyridine-2-carboxamide (22.97 mg, 0.1675 mmol) in NMP (500μL), and DIEA (54.13 mg, 72.95 μL, 0.4188 mmol) at 0° C. was added asolution of2,2-difluoro-5-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-1,3-benzodioxole-4-carbonylchloride (60 mg, 0.1396 mmol) in NMP (200 μL) slowly. The mixture wasstirred at RT for 16 h. The crude product was filtered and purified byreverse phase HPLC (gradient of 10-99% acetonitrile in water containingHCl as a modifier) to yield4-[[2,2-difluoro-5-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-1,3-benzodioxole-4-carbonyl]amino]pyridine-2-carboxamide(24.0 mg, 32%). ESI-MS m/z calc. 530.094, found 530.96 (M+1)⁺; Retentiontime (Method B): 1.85 minutes. ¹H NMR (400 MHz, DMSO-d₆) δ 11.32 (s,1H), 8.55 (d, J=5.5 Hz, 1H), 8.27 (d, J=2.1 Hz, 1H), 8.12 (d, J=2.9 Hz,1H), 7.82 (dd, J=5.6, 2.1 Hz, 1H), 7.68 (s, 1H), 7.50 (d, J=8.9 Hz, 1H),7.20 (d, J=8.8 Hz, 1H), 7.15 (d, J=2.7 Hz, 1H), 6.96 (d, J=9.1 Hz, 1H),6.67 (d, J=8.9 Hz, 1H) ppm.

The compounds set forth in Table 11 were prepared by methods analogousto the preparation of compound 114.

TABLE 11 Additional Compounds Prepared By Methods Analogous to Example15. Cmpd No. Compound Name LC/MS NMR (shifts in ppm) 1155-[[2,2-difluoro-5-[2- ESI-MS m/z ¹H NMR (400 MHz, DMSO-d₆) δ(trideuteriomethoxy)-4- calc. 530.094, 11.26 (s, 1H), 8.84 (d, J =(trifluoromethoxy)phenoxy]- found 530.91 2.4 Hz, 1H), 8.22 (dd, J =1,3-benzodioxole-4- (M + 1)+; 8.6, 2.5 Hz, 1H), 8.08-8.01carbonyl]amino]pyridine-2- Retention time (m, 2H), 7.59 (s, 1H), 7.50(d, carboxamide (Method B): J = 8.9 Hz, 1H), 7.19 (d, J = 1.87 minutes8.8 Hz, 1H), 7.15 (d, J = 2.7 Hz, 1H), 6.96 (d, J = 7.4 Hz, 1H), 6.69(d, J = 8.9 Hz, 1H).

Example 165-[[2-methyl-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(116)

Step 1: 2-bromo-6-fluoro-3-(trifluoromethyl)benzoic acid

To a stirred solution of 2-bromo-4-fluoro-1-(trifluoromethyl)benzene(17.004 g, 10 mL, 67.877 mmol) in anhydrous THF (600 mL) was added LDA(37 mL of 2.0 M, 74.000 mmol) drop-wise over 15 minutes at −78° C. Thereaction mixture was stirred at this temperature for 2 h. The resultingyellow solution was then transferred via cannula onto crushed CO₂ andthe resulting emulsion was stirred gently for 17 h. The solvent wasevaporated in vacuo and the slurry was taken up in NaOH solution (500mL, 1M) and extracted once with diethyl ether (500 mL). The aqueouslayer was acidified to pH=1 and then extracted with diethyl ether (3×500mL). The combined organic layer was washed with brine (200 mL), driedover Na₂SO₄, filtered, and concentrated under reduced pressure to give2-bromo-6-fluoro-3-(trifluoromethyl)benzoic acid (16.3 g, 79%) as anoff-white solid. ESI-MS m/z calc. 285.9253, found 287.1 (M+1)⁺;Retention time: 1.84 minutes. ¹H NMR (500 MHz, DMSO-d6) δ 8.01 (dd,J=8.9, 5.6 Hz, 1H), 7.63 (t, J=8.6 Hz, 1H) ppm.

LCMS Method: Water Cortex 2.7u C18 (3.0 mm×50 mm), Temp: 55c; Flow: 1.2mL/minutes; MP: 100% water with 0.1% trifluoroacetic (TFA) acid then100% acetonitrile with 0.1% TFA acid, grad:5% to 100% B over 4 min, withstay at 100% B for 0.5 min, equilibration to 5% B over 1.5 min.

Step 2: tert-butyl 2-bromo-6-fluoro-3-(trifluoromethyl)benzoate

A stirring mixture of 2-bromo-6-fluoro-3-(trifluoromethyl)benzoic acid(8.0 g, 27.87 mmol), tert-butoxycarbonyl tert-butyl carbonate (9.1 g,41.70 mmol), DMAP (680 mg, 5.566 mmol), and t-BuOH (8 mL) was heated at90° C. for 1 hour. The reaction mixture cooled to RT and directlypurified by silica gel column chromatography using a gradient of 1-10%EtOAc in Hexanes to give tert-butyl2-bromo-6-fluoro-3-(trifluoromethyl)benzoate (8.1 g, 85%) as a whitesolid. ESI-MS m/z calc. 341.98785, found 344.8 (M+1)⁺; Retention time(Method B): 2.02 minutes. ¹H NMR (400 MHz, DMSO-d6) δ 8.03 (dd, J=9.0,5.7 Hz, 1H), 7.64 (t, J=8.6 Hz, 1H), 1.58 (s, 9H) ppm.

Step 3: tert-butyl2-bromo-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoate

A mixture of tert-butyl 2-bromo-6-fluoro-3-(trifluoromethyl)benzoate(500 mg, 1.3115 mmol), 2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenol(360.02 mg, 1.7050 mmol), and K₂CO₃ (362.51 mg, 2.6230 mmol) in DMSO (2mL) was heated at 100° C. for 1 h. The reaction mixture was allowed tocool to RT, poured onto 50 mL of water and extracted with ethyl acetate(3×50 mL). The combined organic layer was washed with brine (50 mL),dried over Na₂SO₄, filtered and concentrated in vacuo to give crudetert-butyl2-bromo-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoate(800 mg, 103%) as a purple oil. ESI-MS m/z calc. 533.03516, found 534.3(M+1)⁺; Retention time: 4.39 minutes; LCMS Method: MerckmilliporeChromolith SpeedROD C18 column (50×4.6 mm) and a dual gradient run from5-100% mobile phase B over 6 minutes. Mobile phase A=water (0.1%CF₃CO₂H). Mobile phase B=acetonitrile (0.1% CF₃CO₂H); LCMS MethodDetail: null.

Step 4: tert-butyl2-methyl-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoate

A mixture of tert-butyl2-bromo-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoate(1.6 g, 2.6953 mmol), methylboronic acid (1.06 g, 17.354 mmol), K₂CO₃(1.2 g, 8.5090 mmol) and Pd(dppf)₂Cl₂ (200 mg, 0.2679 mmol) in dioxane(10 mL) and water (1 mL) was flushed with nitrogen, capped and heated at120° C. for 30 minutes in microwave. The reaction mixture was allowed tocool to RT and diluted with water (50 mL) and extracted with ethylacetate (3×50 mL). The combined organic layer was washed with brine,filtered, and concentrated in vacuo to give tert-butyl2-methyl-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoate(1.3 g, 98%) as a pale yellow solid which was used in next step withoutpurification. ESI-MS m/z calc. 469.1403, found 470.5 (M+1)⁺; Retentiontime: 4.42 minutes. LCMS Method: Merckmillipore Chromolith SpeedROD C18column (50×4.6 mm) and a dual gradient run from 5-100% mobile phase Bover 6 minutes. Mobile phase A=water (0.1% CF₃CO₂H). Mobile phaseB=acetonitrile (0.1% CF₃CO₂H).

Step 5:2-methyl-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoicacid

A solution of tert-butyl2-methyl-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoate(2.6 g, 4.4313 mmol) in THF (10 mL)/Water (5 mL) was added TFA (51.800g, 35 mL, 454.29 mmol) and stirred at rt for 1 h. The reaction mixturewas extracted with ether (3×100 mL). The combined organic layer waswashed with 10% NaHCO₃ solution (50 mL), water (50 mL), brine (50 mL),dried over Na₂SO₄, filtered, and concentrated in vacuo. The resultingpale yellow oil was triturated with DCM (5 mL)/Hexanes (50 mL) and theresulting solid was filtered and dried in vacuo to give2-methyl-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoicacid (1.8 g, 93%) as a white solid. ¹H NMR (500 MHz, DMSO-d6) 7.64 (d,J=8.9 Hz, 1H), 7.26 (d, J=2.8 Hz, 1H), 7.21 (d, J=8.8 Hz, 1H), 7.01(ddd, J=8.8, 2.8, 1.3 Hz, 1H), 6.59 (d, J=8.8 Hz, 1H), 2.40 (d, J=1.8Hz, 3H) ppm.

Step 6:5-[[2-methyl-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(116)

A solution of2-methyl-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoicacid (150 mg, 0.3629 mmol) and DMF (25 μL, 0.3229 mmol) were dissolvedin DCM (3 mL). Oxalyl chloride (250 μL, 2.866 mmol) was slowly addeddropwise to the reaction mixture at RT. After 1 h the reaction mixturewas concentrated under vacuo to give2-methyl-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoylchloride as an oil. This was dissolved in NMP (0.4 mL). This solutionwas slowly added to a prepared solution of 5-aminopyridine-2-carboxamide(19.91 mg, 0.1452 mmol) and DIEA (56.29 mg, 75.86 μL, 0.4355 mmol) inNMP (0.4 mL) at RT. The reaction mixture was allowed to stir overnight.The product was isolated by reverse-phase HPLC (gradient of 10-99%acetonitrile in water containing HCl as a modifier) to afford5-[[2-methyl-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(28.2 mg, 73%). ESI-MS m/z calc. 532.1261, found 533.2 (M+1)⁺; Retentiontime (Method B): 1.85 minutes. ¹H NMR (400 MHz, DMSO-d₆) δ 11.18 (s,1H), 8.90 (d, J=2.4 Hz, 1H), 8.34 (dd, J=8.6, 2.5 Hz, 1H), 8.08-8.01 (m,2H), 7.72 (d, J=8.9 Hz, 1H), 7.57 (s, 1H), 7.31 (d, J=8.8 Hz, 1H), 7.24(d, J=2.7 Hz, 1H), 7.07-6.95 (m, 1H), 6.64 (d, J=8.9 Hz, 1H), 2.46-2.41(m, 3H) ppm.

The compounds set forth in Table 12 were prepared by methods analogousto the preparation of compound 116 in Example 16.

TABLE 12 Additional Compounds Prepared by Methods Analogous to Example16. Cmpd No. Compound Name LC/MS NMR (shifts in ppm) 1174-[[2-methyl-6-[2- ESI-MS m/z ¹H NMR (400 MHz, DMSO-d₆) δ 11.28(trideuteriomethoxy)-4- calc. 532.1261, (s, 1H), 8.55 (d, J = 5.5 Hz,1H), 8.38 (trifluoromethoxy)phenoxy]- found 533.2 (d, J = 2.1 Hz, 1H),8.12 (s, 1H), 7.87 3- (M + 1)+; (dd, J = 5.6, 2.1 Hz, 1H), 7.72 (d, J =(trifluoromethyl)benzo- Retention time 8.9 Hz, 1H), 7.67 (d, J = 2.9 Hz,1H), yl]amino]pyridine-2- (Method C): 7.31 (d, J = 8.8 Hz, 1H), 7.24 (d,J = carboxamide 1.84 minutes 2.7 Hz, 1H), 7.04 (d, J = 10.0 Hz, 1H),6.64 (d, J = 8.8 Hz, 1H), 2.43 (s, 3H).

Example 175-[[6-(3,4-difluoro-2-methoxy-phenoxy)-2-fluoro-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(118)

Step 1:6-(3,4-difluoro-2-methoxy-phenoxy)-2-fluoro-3-(trifluoromethyl)benzoicacid

A solution of 6-bromo-2-fluoro-3-(trifluoromethyl)benzoic acid (1 g,3.484 mmol), 3,4-difluoro-2-methoxy-phenol (557 mg, 3.479 mmol), Cs₂CO₃(2.3 g, 7.059 mmol) in toluene (20 mL) was bubbled with N₂ for 10minutes then CuI (132 mg, 0.6931 mmol) was added. The flask was flushedwith N₂, capped, and heated at 100° C. with vigorous stirring for 1 h.The mixture was allowed to cool then diluted with ethyl acetate andwater. The water layer was acidified with HCl (5.2 mL of 1 M, 5.200mmol) and the product extracted into ethyl acetate. The organic layerwas evaporated to dryness under reduced pressure and the residue waspurified by silica gel column chromatography using a gradient eluent of1-10% MeOH in DCM to give to provide6-(3,4-difluoro-2-methoxy-phenoxy)-2-fluoro-3-(trifluoromethyl)benzoicacid (1.2 g, 92%) as a white solid. ESI-MS m/z calc. 366.03268, found367.0 (M+1)⁺; Retention time (Method B): 1.66 minutes. ¹H NMR (400 MHz,DMSO-d6) δ 7.76 (t, J=8.6 Hz, 1H), 7.39-7.21 (m, 1H), 7.14 (ddd, J=9.3,5.1, 2.2 Hz, 1H), 6.75 (d, J=8.9 Hz, 1H), 3.85 (s, 3H) ppm.

Step 2:5-[[6-(3,4-difluoro-2-methoxy-phenoxy)-2-fluoro-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(118)

A mixture of6-(3,4-difluoro-2-methoxy-phenoxy)-2-fluoro-3-(trifluoromethyl)benzoicacid (102.1 mg, 0.2731 mmol), oxalyl dichloride (23.11 mg, 15.88 μL,0.1821 mmol), DMF (0.3328 mg, 0.3525 μL, 0.004553 mmol), and DCM (1.001mL) was stirred under nitrogen at RT for 1 hour. The reaction mixturewas evaporated to dryness under reduced pressure. To the residue wasadded DCM (500.5 μL), N-ethyl-N-isopropyl-propan-2-amine (35.30 mg,47.57 μL, 0.2731 mmol), and 5-aminopyridine-2-carboxamide (18.73 mg,0.1366 mmol). The reaction mixture was stirred at ambient temperaturefor 1 h. The reaction was diluted with DMSO (500 uL), filtered, andpurified by HPLC (gradient of 10-99% acetonitrile in water containingHCl as a modifier) to give5-[[6-(3,4-difluoro-2-methoxy-phenoxy)-2-fluoro-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(54.8 mg, 41%) as a white solid. ESI-MS m/z calc. 485.08102, found 486.0(M+1)⁺; Retention time (Method B): 1.62 minutes. ¹H NMR (400 MHz,DMSO-d6) δ 11.42 (s, 1H), 8.86 (d, J=2.4 Hz, 1H), 8.32 (dd, J=8.6, 2.5Hz, 1H), 8.07 (d, J=8.5 Hz, 1H), 8.03 (d, J=2.7 Hz, 1H), 7.83 (t, J=8.6Hz, 1H), 7.58 (d, J=2.8 Hz, 1H), 7.39-7.23 (m, 1H), 7.17 (ddd, J=9.3,5.2, 2.1 Hz, 1H), 6.81 (d, J=8.9 Hz, 1H), 3.85 (d, J=1.2 Hz, 3H) ppm.

Example 184-[[4-bromo-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(119)

Step 1: methyl4-bromo-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoate

To methyl 4-bromo-2,6-difluoro-benzoate (6.1 g, 24.30 mmol) was added2-methoxy-4-(trifluoromethoxy)phenol (5.2 g, 24.98 mmol), Cs₂CO₃ (6.3 g,19.34 mmol) and DMF (74 mL). The vial was sealed, the reaction mixturestirred at 80° C. for 1 hour, and the crude mixture cooled to RT. Ethylacetate (˜150 mL) was added and the reaction mixture was washed withbrine (3×75 ml). The organic layer was dried over Na₂SO₄, filtered andconcentrated in vacuo. Column chromatography (silica, 100:0-80:20hexanes:EtOAc) afforded methyl4-bromo-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoate (9.23g, 87%) as a clear oil. ESI-MS m/z calc. 437.9726, found 463.1;Retention time (Method B): 2.09 minutes.

Step 2:4-bromo-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoic acid

To a slurry of methyl4-bromo-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoate (6 g,13.66 mmol) in MeOH (60 mL) and water (60 mL) was added NaOH (5.5 g,137.5 mmol). The reaction mixture was stirred at RT for 5 h. The solventwas evaporated and the residue was taken up in water, cooled in an icebath and quenched with 6N HCl (pH˜ 2) slowly. The resultant solidproduct was filtered and washed with water. The residue was dissolved inDCM/ethyl acetate and dried over MgSO₄, filtered and concentrated. Thefiltrate was extracted by ethyl acetate and dried over MgSO₄ andcombined with the residue to obtain4-bromo-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoic acid(5.6 g, 96%) as clear oil. ESI-MS m/z calc. 423.95694, found 427.0(M+1)⁺; Retention time (Method B):1.82 minutes. The oil was dried underhigh vacuum to for 24 h and taken on without further purification.

Step 3:4-[[4-bromo-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(119)

To a solution of4-bromo-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoic acid(2 g, 4.704 mmol), DMF (100 μL, 1.291 mmol) and DCM (24.0 mL) at 0° C.under N₂ (g) was added oxalyl dichloride (3.3 mL, 37.83 mmol). Thereaction was stirred at 0° C. for 10 minutes and then at RT for 1 h. Themixture was concentrated under reduced pressure and redissolved in NMP(5 mL). This solution was added drop-wise to a suspension of4-aminopyridine-2-carboxamide (700 mg, 5.104 mmol), DMF (720 μL, 9.299mmol), DIEA (5 mL, 28.71 mmol) in NMP (10 mL) under N₂ atmosphere at 0°C. The resulting reaction mixture was slowly warmed to RT and stirred atRT for 18 h. The reaction mixture turned from light brown suspensioninto a dark brown solution with time. The mixture was partitionedbetween water and ethyl acetate. The phases were separated and theaqueous layer was extracted with ethyl acetate (1×). The combinedorganic layer was washed with brine (2×), water (2×) then brine (1×).The organic layer was dried over Na₂SO₄, filtered and concentrated togive light brown foam. The crude was purified by ISCO silicachromatography (80 g silica gel column) eluting with a gradient systemof hexane/EtOAc starting from 100% hexane to 70% EtOAc over 30 minutesto afford4-[[4-bromo-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(710 mg, 28%) as a white solid. ESI-MS m/z calc. 543.0053, found 546.1(M+1)⁺; Retention time (Method B): 1.72 minutes. ¹H NMR (400 MHz,DMSO-d6) δ 11.30 (s, 1H), 8.54 (d, J=5.5 Hz, 1H), 8.29 (d, J=2.1 Hz,1H), 8.10 (d, J=2.8 Hz, 1H), 7.82 (dd, J=5.5, 2.2 Hz, 1H), 7.65 (d,J=2.8 Hz, 1H), 7.52 (dd, J=8.6, 1.6 Hz, 1H), 7.30 (d, J=8.8 Hz, 1H),7.20 (d, J=2.7 Hz, 1H), 7.05-6.97 (m, 1H), 6.75 (d, J=1.6 Hz, 1H), 3.78(s, 3H) ppm.

Example 194-[[6-(3,4-difluoro-2-methoxy-phenoxy)-2-methyl-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(120)

Step 1: 6-fluoro-2-methyl-3-(trifluoromethyl)benzoic acid

To a solution of 2-bromo-6-fluoro-3-(trifluoromethyl)benzoic acid (3.5g, 12.19 mmol) and methylboronic acid (2.189 g, 36.57 mmol) in THF (35mL) was added Cs₂CO₃ (12 g, 36.83 mmol) followed by Pd(dppf)₂Cl₂ (498mg, 0.6098 mmol) under nitrogen gas. The reaction mixture was allowed tostir at 65° C. overnight and then heated under reflux in a 75° C. oilbath for 3 h. The reaction mixture was diluted with EtOAc (75 mL) andwashed with aqueous HCl (0.5 M, 1×75 mL) and brine (1×75 mL). Theorganic layer was dried over Na₂SO₄, filtered and concentrated underreduced pressure. The resultant oil was purified by silica gel columnchromatography using a MeOH/DCM eluent.6-fluoro-2-methyl-3-(trifluoromethyl)benzoic acid (2.27 g, 84%) wasobtained as a ˜1.3:1 mixture of6-fluoro-2-methyl-3-(trifluoromethyl)benzoic acid and6-fluoro-3-(trifluoromethyl)benzoic acid as a crystalline solid. ¹H NMR(400 MHz, DMSO-d6) δ 13.95 (s, 1H), 7.85 (dd, J=8.9, 5.5 Hz, 1H), 7.38(t, J=8.8 Hz, 1H), 2.42 (d, J=1.9 Hz, 3H) ppm.

Step 2:4-[[6-fluoro-2-methyl-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide

6-fluoro-2-methyl-3-(trifluoromethyl)benzoic acid (900 mg, 4.052 mmol)was dissolved in dichloromethane (13 mL). DMF (125 μL, 1.614 mmol) wasadded followed by the slow drop wise addition of oxalyl chloride (2.5mL, 28.66 mmol). The reaction mixture was allowed to stir at RT for 30minutes. The reaction mixture was concentrated under reduced pressure.Additional dichloromethane (˜5 mL) was added, and the solution was againconcentrated to dryness. The remaining residue was taken up in NMP (2.7mL) and was added to a prepared solution of4-aminopyridine-2-carboxamide (833 mg, 6.074 mmol) and DIEA (4.2 mL,24.11 mmol) in NMP (2.7 mL). This reaction mixture was allowed to stirat RT overnight. The reaction mixture was diluted with EtOAc (75 mL) andwashed with water (2×75 mL), aqueous HCl (2×75 mL, 0.5 M) and brine(2×75 mL). The organic layer was dried over sodium sulfate, filtered andconcentrated under reduced pressure. The crude product waschromatographed on silica gel eluting with an EtOAc/hexane gradient toprovide4-[[6-fluoro-2-methyl-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(800 mg, 58%) as a white solid. ESI-MS m/z calc. 341.07874, found 342.1(M+1)⁺; Retention time (Method B): 1.25 minutes. ¹H NMR (400 MHz,DMSO-d6) δ 11.36 (s, 1H), 8.60-8.55 (m, 1H), 8.36 (d, J=2.1 Hz, 1H),8.12 (d, J=2.8 Hz, 1H), 7.92 (dd, J=8.9, 5.5 Hz, 1H), 7.84 (dd, J=5.4,2.2 Hz, 1H), 7.67 (d, J=2.9 Hz, 1H), 7.47 (t, J=8.7 Hz, 1H), 2.44 (d,J=1.8 Hz, 3H) ppm.

Step 3:4-[[6-(3,4-difluoro-2-methoxy-phenoxy)-2-methyl-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(120)

To a solution of4-[[6-fluoro-2-methyl-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(25 mg, 0.07326 mmol) in DMSO (0.5 mL) was added to3,4-difluoro-2-methoxy-phenol (approximately 35.19 mg, 0.2198 mmol).Finely ground K₂CO₃ (30.38 mg, 0.2198 mmol) was then added. The reactionmixture was capped and allowed to stir at 120° C. for 30 minutes then at140° C. for 1.5 h. The product was isolated by mass-triggeredreverse-phase HPLC. Samples were and purified by reverse phase HPLC(gradient of 10-99% acetonitrile in water containing HCl as a modifier)to afford4-[[6-(3,4-difluoro-2-methoxy-phenoxy)-2-methyl-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(7.1 mg, 20%). ESI-MS m/z calc. 481.1061, found 482.2 (M+1)⁺; Retentiontime (Method B): 1.65 minutes. ¹H NMR (400 MHz, DMSO-d₆) δ 11.33 (s,1H), 8.55 (d, J=5.4 Hz, 1H), 8.39 (d, J=2.1 Hz, 1H), 8.12 (s, 1H), 7.86(dd, J=5.5, 2.2 Hz, 1H), 7.73 (d, J=8.9 Hz, 1H), 7.67 (s, 1H), 7.28 (q,J=9.3 Hz, 1H), 7.14-7.06 (m, 1H), 6.77 (d, J=8.9 Hz, 1H), 3.83 (s, 3H),2.44 (s, 3H) ppm.

The compounds set forth in Table 13 were prepared by methods analogousto the preparation of compound 120 in Example 19.

TABLE 13 Additional Compounds Prepared by Methods Analogous to Example19. Cmpd No. Compound Name LC/MS NMR (shifts in ppm) 1214-[[6-(2,3-difluoro-4- ESI-MS m/z ¹H NMR (400 MHz, DMSO-d₆) δ 11.33 (s,isopropoxy-phenoxy)- calc. 509.1374, 1H), 8.55 (d, J = 5.5 Hz, 1H), 8.36(d, J = 2-methyl-3- found 510.2 2.1 Hz, 1H), 8.12 (d, J = 2.7 Hz, 1H),7.86 (trifluoromethyl)benzo- (M + 1)+; (dd, J = 5.6, 2.2 Hz, 1H), 7.75(d, J = 8.9 yl]amino]pyridine-2- Retention time Hz, 1H), 7.67 (d, J =2.8 Hz, 1H), 7.16- carboxamide (Method B): 7.06 (m, 2H), 6.88 (d, J =8.8 Hz, 1H), 4.82- 1.8 minutes 4.54 (m, 1H), 2.43 (s, 3H), 1.30 (d, J =6.0 Hz, 6H). 122 4-[[6-(2-chloro-4- ESI-MS m/z ¹H NMR (400 MHz, DMSO-d₆)δ 11.29 (s, fluoro-phenoxy)-2- calc. 467.06598, 1H), 8.55 (d, J = 5.4Hz, 1H), 8.37 (d, J = methyl-3- found 468.2 2.1 Hz, 1H), 8.12 (d, 1H),7.86 (dd, J = 5.5, (trifluoromethyl)benzo- (M + 1)+; 2.2 Hz, 1H), 7.75(d, J = 8.9 Hz, 1H), 7.72- yl]amino]pyridine-2- Retention time 7.60 (m,2H), 7.49-7.27 (m, 2H), 6.70 carboxamide (Method B): (d, J = 8.8 Hz,1H), 2.45 (s, 3H). 1.65 minutes 123 4-[[2-methyl-6-[4- ESI-MS m/z ¹H NMR(400 MHz, DMSO-d₆) δ 11.31 (s, (trifluoromethoxy)phe- calc. 499.09668,1H), 8.53 (d, J = 5.5 Hz, 1H), 8.34 (d, J = noxy]-3- found 500.2 2.1 Hz,1H), 8.11 (d, J = 2.7 Hz, 1H), 7.83 (trifluoromethyl)benzo- (M + 1)+;(dd, J = 5.5, 2.2 Hz, 1H), 7.79 (d, J = 8.9 yl]amino]pyridine-2-Retention time Hz, 1H), 7.67 (d, J = 2.7 Hz, 1H), 7.46 (d, J =carboxamide (Method B): 8.6 Hz, 2H), 7.34-7.24 (m, 2H), 6.90 (d, 1.79minutes J = 8.8 Hz, 1H), 2.44 (s, 3H). 124 4-[[6-(3-chloro-4- ESI-MS m/z¹H NMR (400 MHz, DMSO-d₆) δ 11.26 (s, isopropoxy-phenoxy)- calc.507.11728, 1H), 8.54 (d, J = 5.5 Hz, 1H), 8.35 (d, J = 2-methyl-3- found508.2 2.1 Hz, 1H), 8.11 (d, J = 2.8 Hz, 1H), 7.84(trifluoromethyl)benzo- (M + 1)+; (dd, J = 5.5, 2.2 Hz, 1H), 7.75 (d, J= 8.9 yl]amino]pyridine-2- Retention time Hz, 1H), 7.67 (d, J = 2.8 Hz,1H), 7.34 (d, J = carboxamide (Method B): 2.8 Hz, 1H), 7.24 (d, J = 9.0Hz, 1H), 1.85 minutes 7.14 (dd, J = 9.0, 2.9 Hz, 1H), 6.82 (d, J = 8.8Hz, 1H), 4.72-4.55 (m, 1H), 2.43 (s, 3H), 1.28 (d, J = 6.0 Hz, 6H). 1254-[[6-[(4-fluoro-2,3- ESI-MS m/z ¹H NMR (400 MHz, DMSO-d₆) δ 11.30 (s,dihydrobenzofuran-7- calc. 475.1155, 1H), 8.55 (d, J = 5.5 Hz, 1H), 8.38(d, J = yl)oxy]-2-methyl-3- found 476.3 2.1 Hz, 1H), 8.13 (s, 1H), 7.87(dd, J = 5.5, (trifluoromethyl)benzo- (M + 1)+; 2.2 Hz, 1H), 7.72 (d, J= 8.9 Hz, 1H), 7.68 yl]amino]pyridine-2- Retention time (s, 1H), 7.04(dd, J = 9.0, 4.7 Hz, 1H), 6.83- carboxamide (Method B): 6.62 (m, 2H),4.64 (t, J = Hz, 2H), 1.62 minutes; 3.29 (t, J = 8.7 Hz, 2H), 2.41 (s,3H). 126 4-[[6-(3,4- ESI-MS m/z ¹H NMR (400 MHz, DMSO-d₆) δ 11.28 (s,difluorophenoxy)-2- calc. 451.09552, 1H), 8.54 (d, J = 5.5 Hz, 1H), 8.34(d, J = methyl-3- found 452.2 2.2 Hz, 1H), 8.12 (s, 1H), 7.83 (dd, J =5.5, (trifluoromethyl)benzo- (M + 1)+; 2.2 Hz, 1H), 7.78 (d, J = 8.9 Hz,1H), 7.68 yl]amino]pyridine-2- Retention time (s, 1H), 7.53 (q, J = 9.5Hz, 1H), 7.47- carboxamide (Method B): 7.32 (m, 1H), 7.12-6.99 (m, 1H),6.92 (d, 1.63 minutes J = 8.8 Hz, 1H), 2.44 (s, 3H). 1274-[[6-(3-chloro-4- ESI-MS m/z ¹H NMR (400 MHz, DMSO-d₆) δ 11.29 (s,fluoro-phenoxy)-2- calc. 467.06598, 1H), 8.54 (d, J = 5.5 Hz, 1H), 8.35(d, J = methyl-3- found 468.2 2.1 Hz, 1H), 8.12 (s, 1H), 7.83 (dd, J =5.5, (trifluoromethyl)benzo- (M + 1)+; 2.2 Hz, 1H), 7.78 (d, J = 8.9 Hz,1H), 7.68 yl]amino]pyridine-2- Retention time (s, 1H), 7.57-7.43 (m,2H), 7.30-7.15 carboxamide (Method B): (m, 1H), 6.92 (d, J = 8.8 Hz,1H), 2.44 (s, 1.71 minutes 3H). 128 4-[[6-[2-fluoro-4- ESI-MS m/z ¹H NMR(400 MHz, DMSO-d₆) δ 11.42 (s, (trifluoromethoxy)phe- calc. 517.0873,1H), 8.55 (d, J = 5.5 Hz, 1H), 8.38 (d, J = noxy]-2-methyl-3- found518.2 2.1 Hz, 1H), 8.16 (s, 1H), 7.86 (dd, J = 5.5,(trifluoromethyl)benzo- (M + 1)+; 2.2 Hz, 1H), 7.79 (d, J = 8.9 Hz, 1H),7.75- yl]amino]pyridine-2- Retention time 7.64 (m, 2H), 7.48 (t, J = 9.0Hz, 1H), carboxamide (Method B): 7.35 (d, J = 9.1 Hz, 1H), 6.91 (d, J =8.8 1.79 minutes Hz, 1H), 2.45 (s, 3H). 129 4-[[6-(4-fluoro-2- ESI-MSm/z ¹H NMR (400 MHz, DMSO-d₆) δ 11.31 (s, methyl-phenoxy)-2- calc.447.1206, 1H), 8.54 (d, J = 5.4 Hz, 1H), 8.38 (d, J = methyl-3- found448.3 2.1 Hz, 1H), 8.12 (d, J = 2.8 Hz, 1H), 7.86(trifluoromethyl)benzo- (M + 1)+; (dd, J = 5.5, 2.2 Hz, 1H), 7.72 (d, J= 8.9 yl]amino]pyridine-2- Retention time Hz, 1H), 7.67 (d, 1H), 7.24(dd, 1H), 7.20- carboxamide (Method B): 7.07 (m, 2H), 6.60 (d, J = 8.8Hz, 1H), 2.44 1.68 minutes (s, 3H), 2.12 (s, 3H). 1304-[[6-(4-ethoxy-2,3- ESI-MS m/z 1H NMR (400 MHz, DMSO-d6) δ 11.31 (s,difluoro-phenoxy)-2- calc. 495.12173, 1H), 8.54 (d, J = 5.5 Hz, 1H),8.36 (d, J = methyl-3- found 496.2 2.0 Hz, 1H), 8.10 (d, J = 2.8 Hz,1H), 7.86 (trifluoromethyl)benzo- (M + 1)+; (dd, J = 5.5, 2.1 Hz, 1H),7.74 (d, J = 8.9 yl]amino]pyridine-2- Retention time Hz, 1H), 7.65 (d, J= 2.9 Hz, 1H), 7.18- carboxamide (Method B): 7.03 (m, 2H), 6.86 (d, J =8.9 Hz, 1H), 4.14 1.72 minutes (q, J = 7.0 Hz, 2H), 2.43 (s, 3H), 1.36(t, J = 7.0 Hz, 3H). 131 4-[[6-(2,4- ESI-MS m/z ¹H NMR (400 MHz,DMSO-d₆) δ 11.34 (s, difluorophenoxy)-2- calc. 451.09552, 1H), 8.55 (d,J = 5.5 Hz, 1H), 8.37 (d, J = methyl-3- found 452.2 2.1 Hz, 1H), 8.13(s, 1H), 7.86 (dd, J = 5.5, (trifluoromethyl)benzo- (M + 1)+; 2.2 Hz,1H), 7.76 (d, J = 8.9 Hz, 1H), 7.68 yl]amino]pyridine-2- Retention time(d, J = 2.6 Hz, 1H), 7.61-7.49 (m, 1H), carboxamide (Method B):7.49-7.37 (m, 1H), 7.20 (t, J = 8.6 Hz, 1.59 minutes 1H), 6.80 (d, J =8.8 Hz, 1H), 2.44 (s, 3H). 132 4-[[6-(2-fluoro-4- ESI-MS m/z ¹H NMR (400MHz, DMSO-d₆) δ 11.22 (s, isopropoxy-phenoxy)- calc. 491.14682, 1H),8.55 (d, J = 5.5 Hz, 1H), 8.40 (d, J = 2-methyl-3- found 492.2 2.1 Hz,1H), 8.11 (d, 1H), 7.87 (dd, J = 5.5, (trifluoromethyl)benzo- (M + 1)+;2.2 Hz, 1H), 7.71 (d, J = 8.9 Hz, 1H), 7.66 yl]amino]pyridine-2-Retention time (d, 1H), 7.36-7.17 (m, 1H), 7.07 (d, J = carboxamide(Method B): 8.5 Hz, 1H), 6.99 (t, J = 9.2 Hz, 1H), 6.62 1.74 minutes (d,J = 8.8 Hz, 1H), 4.68-4.49 (m, 1H), 2.43 (s, 3H), 1.14 (d, J = 6.0 Hz,6H). 133 4-[[2-methyl-6-[2- ESI-MS m/z 1H NMR (400 MHz, DMSO-d6) δ 11.30(s, methyl-4- calc. 513.1123, 1H), 8.54 (d, J = 5.5 Hz, 1H), 8.36 (d, J= (trifluoromethoxy)phe- found 513.95 2.1 Hz, 1H), 8.10 (d, J = 2.9 Hz,1H), 7.84 noxy]-3- (M + 1)+; (dd, J = 5.5, 2.2 Hz, 1H), 7.75 (d, J = 8.9(trifluoromethyl)benzo- Retention time Hz, 1H), 7.65 (d, J = 2.9 Hz,1H), 7.39 (d, J = yl]amino]pyridine-2- (Method B): 2.9 Hz, 1H), 7.29(dd, J = 8.9, 2.9 Hz, carboxamide 1.96 minutes 1H), 7.22 (d, J = 8.9 Hz,1H), 6.71 (d, J = 8.8 Hz, 1H), 2.44 (d, J = 1.7 Hz, 3H), 2.16 (s, 3H).134 4-[[6-(4-chloro-2- ESI-MS m/z 1H NMR (400 MHz, DMSO-d6) δ 11.26 (d,methoxy-phenoxy)-2- calc. 479.08597, J = 3.4 Hz, 1H), 8.54 (d, J = 5.5Hz, 1H), methyl-3- found 480.0 8.38 (t, J = 1.6 Hz, 1H), 8.11 (s, 1H),7.87 (trifluoromethyl)benzo- (M + 1)+; (dd, J = 5.5, 2.1 Hz, 1H), 7.70(d, J = 8.9 yl]amino]pyridine-2- Retention time Hz, 1H), 7.66 (s, 1H),7.29 (d, J = 2.4 Hz, carboxamide (Method B): 1H), 7.21 (d, J = 8.5 Hz,1H), 7.08 (dd, J = 1.8 minutes 8.5, 2.4 Hz, 1H), 6.63 (d, J = 8.8 Hz,1H), 3.77 (s, 3H), 2.42 (d, J = 1.7 Hz, 3H). 135 4-[[6-(4-chloro-2-ESI-MS m/z 1H NMR (400 MHz, DMSO-d6) δ 11.31 (s, fluoro-phenoxy)-2-calc. 467.06598, 1H), 8.54 (d, J = 5.5 Hz, 1H), 8.35 (d, J = methyl-3-found 467.95 2.1 Hz, 1H), 8.10 (d, J = 2.7 Hz, 1H), 7.85(trifluoromethyl)benzo- (M + 1)+; (dd, J = 5.5, 2.2 Hz, 1H), 7.77 (d, J= 8.9 yl]amino]pyridine-2- Retention time Hz, 1H), 7.73-7.62 (m, 2H),7.42-7.32 carboxamide (Method B): (m, 2H), 6.88 (d, J = 8.8 Hz, 1H),2.44 (d, J = 1.8 minutes 1.7 Hz, 3H). 136 4-[[6-(4-chloro-2- ESI-MS m/z1H NMR (400 MHz, DMSO-d6) δ 11.30 (s, methyl-phenoxy)-2- calc.463.09106, 1H), 8.54 (d, J = 5.5 Hz, 1H), 8.37 (d, J = methyl-3- found463.95 2.0 Hz, 1H), (trifluoromethyl)benzo- (M + 1)+; 8.10 (d, J = 2.8Hz, 1H), 7.84 (dd, J = 5.5, yl]amino]pyridine-2- Retention time 2.2 Hz,1H), 7.73 (d, J = 8.9 Hz, 1H), 7.65 carboxamide (Method B): (d, J = 2.8Hz, 1H), 7.44 (dd, J = 2.6, 0.9 Hz, 1.88 minutes 1H), 7.34 (dd, J = 8.7,2.7 Hz, 1H), 7.13 (d, J = 8.6 Hz, 1H), 6.68 (d, J = 8.8 Hz, 1H), 2.44(d, J = 1.7 Hz, 3H), 2.12 (s, 3H). 137 4-[[6-(4-fluoro-2- ESI-MS m/z 1HNMR (400 MHz, DMSO-d6) δ 11.25 (s, methoxy-phenoxy)-2- calc. 463.1155,1H), 8.55 (d, J = 5.5 Hz, 1H), 8.39 (d, J = methyl-3- found 464.05 2.1Hz, 1H), 8.11 (d, J = 2.8 Hz, 1H), 7.88 (trifluoromethyl)benzo- (M +1)+; (dd, J = 5.5, 2.2 Hz, 1H), 7.73-7.63 (m, yl]amino]pyridine-2-Retention time 2H), 7.23 (dd, J = 8.9, 5.9 Hz, 1H), 7.15 (dd,carboxamide (Method B): J = 10.7, 2.9 Hz, 1H), 6.85 (td, J = 8.5, 2.91.73 minutes Hz, 1H), 6.58 (d, J = 8.8 Hz, 1H), 3.76 (s, 3H), 2.42 (d, J= 1.7 Hz, 3H). 138 4-[[6-[3-chloro-4- ESI-MS m/z ¹H NMR (400 MHz,DMSO-d₆) δ 11.30 (s, (trifluoromethoxy)phe- calc. 533.0577, 1H), 8.53(d, J = 5.4 Hz, 1H), 8.33 (d, J = noxy]-2-methyl-3- found 533.91 2.1 Hz,1H), 8.11 (d, J = 2.9 Hz, 1H), 7.87- (trifluoromethyl)benzo- (M + 1)+;7.75 (m, 2H), 7.72-7.60 (m, 2H), 7.56 yl]amino]pyridine-2- Retentiontime (d, J = 2.9 Hz, 1H), 7.26 (dd, J = 9.1, 3.0 carboxamide (Method B):Hz, 1H), 7.05 (d, J = 8.8 Hz, 1H), 2.45 (s, 1.97 minutes 3H). 1394-[[6-[3-fluoro-4- ESI-MS m/z (trifluoromethoxy)phe- calc. 517.0873,noxy]-2-methyl-3- found 518.0 (trifluoromethyl)benzo- (M + 1)+;yl]amino]pyridine-2- Retention time carboxamide (Method B): 1.91 minutes140 4-[[2-methyl-3- ESI-MS m/z ¹H NMR (400 MHz, DMSO-d₆) δ 11.35 (s,(trifluoromethyl)-6- calc. 469.08612, 1H), 8.55 (d, J = 5.5 Hz, 1H),8.36 (d, J = (2,3,4- found 470.0 2.1 Hz, 1H), 8.11 (d, 1H), 7.85 (dd, J= 5.5, trifluorophenoxy)benzo- (M + 1)+; 2.2 Hz, 1H), 7.77 (d, J = 8.9Hz, 1H), 7.67 yl]amino]pyridine-2- Retention time (d, J = 2.9 Hz, 1H),7.51-7.35 (m, 1H), carboxamide (Method B): 7.33-7.15 (m, 1H), 6.98 (d, J= 8.8 Hz, 1.76 minutes 1H), 2.44 (s, 3H). 141 4-[[6-(4-fluoro-2,3-ESI-MS m/z 1H NMR (400 MHz, DMSO-d6) δ 11.31 (s, dimethyl-phenoxy)-2-calc. 461.13626, 1H), 8.54 (d, J = 5.5 Hz, 1H), 8.38 (d, J = methyl-3-found 462.0 2.1 Hz, 1H), 8.10 (d, J = 2.9 Hz, 1H), 7.86(trifluoromethyl)benzo- (M + 1)+; (dd, J = 5.5, 2.2 Hz, 1H), 7.70 (d, J= 8.9 yl]amino]pyridine-2- Retention time Hz, 1H), 7.65 (d, J = 3.0 Hz,1H), 7.11 (t, J = carboxamide (Method B): 9.0 Hz, 1H), 7.01 (dd, J =8.9, 4.9 Hz, 1.87 minutes 1H), 6.56 (d, J = 8.8 Hz, 1H), 2.44 (d, J =1.7 Hz, 3H), 2.16 (d, J = 2.1 Hz, 3H), 2.07 (d, J = 4.7 Hz, 3H). 1424-[[6-(2,4-dichloro-6- ESI-MS m/z methyl-phenoxy)-2- calc. 497.0521,methyl-3- found 497.95 (trifluoromethyl)benzo- (M + 1)+;yl]amino]pyridine-2- Retention time carboxamide (Method B): 1.93 minutes143 4-[[2-methyl-3- ESI-MS m/z ¹H NMR (400 MHz, DMSO-d₆) δ 11.39 (s,(trifluoromethyl)-6- calc. 469.08612, 1H), 8.56 (d, J = 5.5 Hz, 1H),8.39 (d, J = (2,4,6- found 470.0 2.1 Hz, 1H), 8.14 (s, 1H), 7.87 (dd, J= 5.6, trifluorophenoxy)benzo- (M + 1)+; 2.2 Hz, 1H), 7.75 (d, J = 8.9Hz, 1H), 7.69 yl]amino]pyridine-2- Retention time (s, 1H), 7.60-7.39 (m,2H), 6.90 (d, J = carboxamide (Method B): 8.9 Hz, 1H), 2.43 (s, 3H).1.72 minutes 144 4-[[6-(4-chloro-2,6- ESI-MS m/z 1H NMR (400 MHz,DMSO-d6) δ 11.32 (s, dimethyl-phenoxy)-2- calc. 477.1067, 1H), 8.55 (d,J = 5.5 Hz, 1H), 8.41 (d, J = methyl-3- found 478.0 2.1 Hz, 1H), 8.11(d, J = 2.8 Hz, 1H), 7.87 (trifluoromethyl)benzo- (M + 1)+; (dd, J =5.5, 2.2 Hz, 1H), 7.71-7.63 (m, yl]amino]pyridine-2- Retention time 2H),7.29 (s, 2H), 6.42 (d, J = 8.8 Hz, 1H), carboxamide (Method B): 2.44 (d,J = 1.6 Hz, 3H), 2.07 (d, J = 1.4 Hz, 1.96 minutes 6H). 1454-[[6-(2,6-dimethoxy- ESI-MS m/z 1H NMR (400 MHz, DMSO-d6) δ 11.08 (s,4-methyl-phenoxy)-2- calc. 489.15115, 1H), 8.53 (d, J = 5.5 Hz, 1H),8.41 (d, J = methyl-3- found 490.05 2.1 Hz, 1H), 8.09 (d, J = 2.8 Hz,1H), 7.88 (trifluoromethyl)benzo- (M + 1)+; (dd, J = 5.5, 2.2 Hz, 1H),7.67-7.60 (m, yl]amino]pyridine-2- Retention time 2H), 6.63 (s, 2H),6.47 (d, J = 8.8 Hz, 1H), carboxamide (Method B): 3.70 (s, 6H), 2.40 (d,J = 1.7 Hz, 3H), 2.33 1.77 minutes (s, 3H). 146 4-[[6-[2-chloro-4-ESI-MS m/z 1H NMR (400 MHz, DMSO-d6) δ 11.30 (s, (trifluoromethoxy)phe-calc. 533.0577, 1H), 8.54 (d, J = 5.5 Hz, 1H), 8.35 (d, J =noxy]-2-methyl-3- found 534.0 2.2 Hz, 1H), 8.19-8.00 (m, 1H), 7.84 (dd,J = (trifluoromethyl)benzo- (M + 1)+; 5.6, 2.2 Hz, 1H), 7.82-7.73 (m,2H), yl]amino]pyridine-2- Retention time 7.69-7.62 (m, 1H), 7.53-7.39(m, 2H), carboxamide (Method B): 6.84 (d, J = 8.8 Hz, 1H), 2.45 (s, 3H).1.84 minutes 147 4-[[6-[3-fluoro-2- ESI-MS m/z 1H NMR (400 MHz, DMSO-d6)δ 11.31 (s, methoxy-4- calc. 547.09784, 1H), 8.54 (d, J = 5.5 Hz, 1H),8.36 (d, J = (trifluoromethoxy)phe- found 548.2 2.1 Hz, 1H), 8.09 (d, J= 2.9 Hz, 1H), 7.84 noxy]-2-methyl-3- (M + 1)+; (dd, J = 5.5, 2.2 Hz,1H), 7.76 (d, J = 8.9 (trifluoromethyl)benzo- Retention time Hz, 1H),7.65 (d, J = 2.8 Hz, 1H), 7.38 yl]amino]pyridine-2- (Method B): (ddd, J= 9.4, 8.1, 1.3 Hz, 1H), 7.13 (dd, J = carboxamide 1.83 minutes 9.3, 2.2Hz, 1H), 6.89 (d, J = 8.8 Hz, 1H), 3.83 (d, J = 1.0 Hz, 3H), 2.45 (d, J= 1.7 Hz, 3H). 148 4-[[6-[2-cyclopropyl- ESI-MS m/z 1H NMR (400 MHz,DMSO-d6) δ 11.30 (s, 4- calc. 539.128, 1H), 8.54 (d, J = 5.5 Hz, 1H),8.36 (d, J = (trifluoromethoxy)phe- found 540.3 2.1 Hz, 1H), 8.10 (d, J= 2.8 Hz, 1H), 7.84 noxy]-2-methyl-3- (M + 1)+; (dd, J = 5.5, 2.2 Hz,1H), 7.76 (d, J = 8.9 (trifluoromethyl)benzo- Retention time Hz, 1H),7.65 (d, J = 2.9 Hz, 1H), 7.29- yl]amino]pyridine-2- (Method B): 7.19(m, 2H), 6.98 (d, J = 2.4 Hz, 1H), 6.71 carboxamide 2.02 minutes (d, J =8.8 Hz, 1H), 2.44 (d, J = 1.6 Hz, 3H), 1.98 (tt, J = 8.4, 5.2 Hz, 1H),0.91- 0.81 (m, 2H), 0.74-0.65 (m, 2H). 149 4-[[6-(3,4-difluoro-2- ESI-MSm/z 1H NMR (400 MHz, DMSO-d6) δ 11.31 (s, methyl-phenoxy)-2- calc.465.11118, 1H), 8.54 (d, J = 5.5 Hz, 1H), 8.36 (d, J = methyl-3- found466.1 2.0 Hz, 1H), 8.09 (s, 1H), 7.84 (dd, J = 5.5,(trifluoromethyl)benzo- (M + 1)+; 2.2 Hz, 1H), 7.73 (d, J = 8.9 Hz, 1H),7.65 yl]amino]pyridine-2- Retention time (s, 1H), 7.38 (q, J = 9.4 Hz,1H), 7.06- carboxamide (Method B): 6.97 (m, 1H), 6.72 (d, J = 8.8 Hz,1H), 2.44 1.79 minutes (d, J = 1.8 Hz, 3H), 2.09 (d, J = 2.2 Hz, 3H).

Example 204-[[2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]-1-oxido-pyridin-1-ium-2-carboxamide(150)

To a stirred slurry of4-[[2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(200 mg, 0.3736 mmol) in anhydrous DCM (1.8 mL) under N₂ at 0° C. wasadded 3-chlorobenzenecarboperoxoic acid (253 mg, 1.129 mmol). Thereaction was allowed to warm up to RT and stirred for 13 h. The solventwas evaporated under reduced pressure. The crude material was purifiedby silica gel chromatography EtOAc/hexanes as eluant to yield4-[[2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]-1-oxido-pyridin-1-ium-2-carboxamide(190 mg, 93%) as a white solid. ESI-MS m/z calc. 549.0771, found 549.9(M+1)⁺; Retention time (Method C): 2.36 minutes. ¹H NMR (400 MHz,DMSO-d6) δ 11.57 (s, 1H), 10.59 (d, J=4.6 Hz, 1H), 8.55 (d, J=3.2 Hz,1H), 8.38 (d, J=7.2 Hz, 1H), 8.28 (d, J=4.5 Hz, 1H), 7.87 (dd, J=7.2,3.2 Hz, 1H), 7.82 (t, J=8.6 Hz, 1H), 7.37 (d, J=8.8 Hz, 1H), 7.27 (d,J=2.7 Hz, 1H), 7.09-7.01 (m, 1H), 6.69 (d, J=8.9 Hz, 1H), 3.79 (s, 3H)ppm.

Example 214-[[6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(151)

Step 1: tert-butyl2-bromo-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoate

A stirring mixture of tert-butyl2-bromo-6-fluoro-3-(trifluoromethyl)benzoate (3.0 g, 8.744 mmol),2-methoxy-4-(trifluoromethoxy)phenol (2.1 g, 10.09 mmol), K₂CO₃ (2.4 g,17.37 mmol), and DMSO (12 mL) was heated at 100° C. for 1 hour. Thereaction mixture was cooled to room temperature and was then directlypurified by silica gel column chromatography using a gradient of 1-100%EtOAc in hexanes to give tert-butyl2-bromo-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoate(4.1 g, 87%) as a clear oil. ¹H NMR (400 MHz, DMSO-d6) δ 7.79 (d, J=8.9Hz, 1H), 7.36-7.17 (m, 2H), 7.12-6.94 (m, 1H), 6.83 (d, J=8.9 Hz, 1H),3.81 (s, 3H), 1.53 (s, 9H) ppm.

Step 2: tert-butyl6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-3-(trifluoromethyl)benzoate

A microwave vial was loaded with tert-butyl2-bromo-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoate(1.0 g, 1.882 mmol), methylboronic acid (563 mg, 9.405 mmol), ferrous;cyclopenta-1,4-dien-1-yl(diphenyl)phosphane; dichloromethane;dichloropalladium (154 mg, 0.1886 mmol), and K₂CO₃ (780 mg, 5.644 mmol).The reaction vial was capped, purged with nitrogen, and 1,4-dioxane (6.0mL) and water (600 μL) were added via syringe. The reaction was heatedat 120° C. (oil bath) for 30 minutes. The reaction mixture was cooled toroom temperature and was then directly purified by silica gel columnchromatography using a gradient of 1-100% EtOAc in hexanes to givetert-butyl6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-3-(trifluoromethyl)benzoate(780 mg, 89%) as a clear oil. ¹H NMR (400 MHz, DMSO-d6) δ 7.66 (d, J=8.9Hz, 1H), 7.25 (d, J=2.7 Hz, 1H), 7.15 (d, J=8.8 Hz, 1H), 7.08-6.92 (m,1H), 6.68 (d, J=8.8 Hz, 1H), 3.81 (s, 3H), 2.38 (d, J=2.1 Hz, 3H), 1.50(s, 9H) ppm.

Step 3:6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-3-(trifluoromethyl)benzoicacid

A solution of tert-butyl6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-3-(trifluoromethyl)benzoate(4.0 g, 8.577 mmol), TFA (100 mL, 1.298 mol), water (6 mL, 333.1 mmol),and THF (16 mL), was stirred at room temperature for 1 hour. Thesolution was evaporated to dryness under reduced pressure and theresidue was purified by silica gel column chromatography using agradient eluent of 1-10% MeOH in dichloromethane to give6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-3-(trifluoromethyl)benzoicacid (3.4 g, 92%) as a light brown semisolid. ¹H NMR (400 MHz, DMSO-d6)δ 13.51 (s, 1H), 7.64 (d, J=8.8 Hz, 1H), 7.25 (d, J=2.7 Hz, 1H), 7.21(d, J=8.8 Hz, 1H), 7.12-6.90 (m, 1H), 6.59 (d, J=8.8 Hz, 1H), 3.80 (s,3H), 2.40 (s, 3H) ppm. ESI-MS m/z calc. 410.0589, found 411.0 (M+1)⁺;Retention time (Method B): 1.87 minutes.

Step 4:6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-3-(trifluoromethyl)benzoylchloride

6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-3-(trifluoromethyl)benzoicacid (1.11 g, 2.706 mmol) was dissolved in dichloromethane (18 mL). DMF(25 μL, 0.3229 mmol) was added. Oxalyl chloride (1.65 mL, 18.91 mmol)was slowly added dropwise while stirring the reaction mixture in a 0° C.ice bath. The ice bath was then removed, and the reaction mixture wasallowed to stir at room temperature for 1 hour. Volatiles were thenremoved under reduced pressure. Additional dichloromethane was added(˜20 mL), and the solution was again concentrated to dryness.6-[2-Methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-3-(trifluoromethyl)benzoylchloride was obtained as a colorless oil which was used directly in thenext step.

Step 5:4-[[6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(151)

A solution of6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-3-(trifluoromethyl)benzoylchloride (500 mg, 1.166 mmol) in NMP (4 mL) was added to a preparedsolution of 4-aminopyridine-2-carboxamide (320 mg, 2.333 mmol) and DIEA(1.22 mL, 7.004 mmol) in NMP (4 mL). The reaction mixture was allowed tostir at room temperature overnight. It was then diluted with EtOAc (75mL) and washed with water (2×75 mL) and brine (3×75 mL). The organiclayer was dried over sodium sulfate, filtered and concentrated underreduced pressure. The crude product was chromatographed on silica gelcolumn eluting with a 0-70% EtOAc/hexane gradient to provide4-[[6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(202 mg, 32%) as a white solid. ¹H NMR (400 MHz, DMSO-d6) δ 11.25 (s,1H), 8.54 (d, J=5.5 Hz, 1H), 8.37 (d, J=2.1 Hz, 1H), 8.09 (d, J=2.9 Hz,1H), 7.86 (dd, J=5.5, 2.1 Hz, 1H), 7.71 (d, J=8.9 Hz, 1H), 7.64 (d,J=2.8 Hz, 1H), 7.30 (d, J=8.8 Hz, 1H), 7.23 (d, J=2.6 Hz, 1H), 7.06-7.00(m, 1H), 6.64 (d, J=8.8 Hz, 1H), 3.78 (s, 3H), 2.43 (s, 3H) ppm. ESI-MSm/z calc. 529.10724, found 530.3 (M+1)⁺; Retention time (Method B): 1.79minutes.

The compounds set forth in Table 14 were prepared by methods analogousto the preparation of compound 151 in Example 21.

TABLE 14 Additional Compounds Prepared by Methods Analogous to Example21. Cmpd No. Compound Name LC/MS NMR (shifts in ppm) 1524-[[6-(2,3-difluoro-4- ESI-MS m/z 1H NMR (400 MHz, DMSO-d6) δ 11.15 (s,isopropoxy- calc. 529.10724, 1H), 8.89 (d, J = 2.4 Hz, 1H), 8.33 (dd, J= phenoxy)-2-methyl- found 530.2 8.6, 2.4 Hz, 1H), 8.11-7.95 (m, 2H),7.71 (d, 3- (M + 1)+; J = 8.9 Hz, 1H), 7.55 (s, 1H), 7.30 (d, J = 8.8(trifluoromethyl)benzo- Retention time Hz, 1H), 7.23 (d, J = 2.7 Hz,1H), 7.08-6.99 yl]amino]pyridine- (Method B): (m, 1H), 6.64 (d, J = 8.8Hz, 1H), 3.78 (s, 2-carboxamide 1.79 minutes 3H), 2.44 (s, 3H). 1534-[[6-[2-methoxy-4- ESI-MS m/z 1H NMR (400 MHz, DMSO-d6) δ 10.45 (s,(trifluoromethoxy)phe- calc. 543.12286, 1H), 8.48 (s, 1H), 8.45 (s, 1H),8.06 (s, 1H), noxy]-2-methyl-3- found 544.2 7.70 (d, J = 8.9 Hz, 1H),7.60 (s, 1H), 7.31 (d, (trifluoromethyl)benzo- (M + 1)+; J = 8.7 Hz,1H), 7.25 (s, 1H), 7.04 (d, J = 8.9 yl]amino]-5-methyl- Retention timeHz, 1H), 6.63 (d, J = 8.9 Hz, 1H), 3.80 (s, pyridine-2- (Method B): 3H),2.31 (s, 3H). carboxamide 1.8 minutes

Example 224-[[4-(3-furyl)-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(154)

Step 1: 4-bromo-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzaldehyde

To a solution of 4-bromo-2-fluoro-benzaldehyde (3.70 g, 18.23 mmol) inDMF (35 mL) was added Cs₂CO₃ (7.50 g, 23.02 mmol) and2-methoxy-4-(trifluoromethoxy)phenol (4.17 g, 20.04 mmol). The reactionmixture was stirred at RT for 16 h. The reaction mixture was partitionedbetween ethyl acetate and water. The organic layer was washed withwater, aqueous NaHCO₃ (50%) and brine, then dried over MgSO₄, filteredand concentrated in vacuo. Purification by silica gel columnchromatography using a EtOAc/hexanes eluent provided4-bromo-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzaldehyde (6.77 g,95%). ESI-MS m/z calc. 389.97147, found 392.9 (M+1)⁺; Retention time(Method A): 0.8 minutes. ¹H NMR (400 MHz, DMSO-d6) δ 10.43 (s, 1H), 7.75(d, J=8.3 Hz, 1H), 7.48-7.43 (m, 1H), 7.40 (d, J=8.8 Hz, 1H), 7.28 (d,J=2.7 Hz, 1H), 7.05 (ddd, J=8.8, 2.8, 1.3 Hz, 1H), 6.88 (d, J=1.7 Hz,1H), 3.80 (s, 3H) ppm.

Step 2: 4-bromo-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoic acid

A mixture of4-bromo-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzaldehyde (6.74 g,17.23 mmol) and NaH₂PO₄ (3.10 g, 25.84 mmol) in tert-butyl alcohol (60mL)/water (35 mL)/acetonitrile (35 mL) at 0° C. was treated with2-methylbut-2-ene (8.0 mL, 75.51 mmol) followed by the portion-wiseaddition of sodium chlorite (2.92 g, 25.83 mmol) over 10 minutes. Themixture was allowed to warm to RT and stirred for 16 h. AdditionalNaH₂PO₄ (3.10 g, 25.84 mmol) and sodium chlorite (2.92 g, 25.83 mmol)were added and the reaction mixture stirred for 30 minutes. The reactionmixture was acidified to pH 1-2 with aqueous HCl (175 mL of 1 M, 175.0mmol) and partitioned with ethyl acetate. Excess sodium sulfite solidwas added to the aqueous layer to remove the faint yellow color. The twolayers were separated and the aqueous layer was extracted with ethylacetate (3×25 mL). The combined organics were washed with brine, driedover Na₂SO₄, filtered and concentrated to an off-white solid. The solidwas stirred/triturated with hexane (100 mL) for 1 h then filtered toprovide 4-bromo-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoic acid(6.70 g, 96%) as a white solid. ESI-MS m/z calc. 405.96637, found 407.9(M+1)⁺; Retention time (Method A): 0.72 minutes. ¹H NMR (400 MHz,DMSO-d6) δ 13.03 (s, 1H), 7.75 (d, J=8.4 Hz, 1H), 7.39 (dd, J=8.3, 1.8Hz, 1H), 7.21 (d, J=2.7 Hz, 1H), 7.09 (d, J=8.8 Hz, 1H), 6.99-6.94 (m,1H), 6.88 (d, J=1.8 Hz, 1H), 3.80 (s, 3H) ppm.

Step 3:4-[[4-bromo-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide

4-Bromo-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoic acid (2.011 g,4.939 mmol) in anhydrous DCM (16 mL) under nitrogen was treated with DMF(20 μL, 0.2583 mmol), cooled in an ice bath and the suspension treateddropwise with oxalyl chloride (700 μL, 8.024 mmol). The solution wasstirred for 15 minutes and then at 35° C. for 15 minutes (until nofurther gas evolution was observed). The acid chloride solution wasconcentrated under vacuo and the resulting solid was dissolved in DCM (5mL) then added drop-wise to a cold solution of4-aminopyridine-2-carboxamide (0.812 g, 5.921 mmol) and DIEA (2.2 mL,12.63 mmol) in NMP (20 mL). The clear orange-colored reaction mixturewas then stirred at RT for 2 h. The reaction was concentrated in vacuo,diluted with ethyl acetate and washed with water (2×), aqueous NaHCO₃(50%) and brine. The organic phase was dried over Na2SO4, filtered andconcentrated. The resulting light orange solid was triturated with coldDCM (25 mL) and filtered. The solid was rinsed with minimal cold DCM toremove color and air dried to provide4-[[4-bromo-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(1.210 g, 47%). ESI-MS m/z calc. 525.0147, found 527.0 (M+1)⁺; Retentiontime (Method A): 0.71 minutes. ¹H NMR (400 MHz, DMSO-d6) δ 10.88 (s,1H), 8.51 (d, J=5.5 Hz, 1H), 8.30 (d, J=2.1 Hz, 1H), 8.08 (d, J=2.9 Hz,1H), 7.85 (dd, J=5.5, 2.1 Hz, 1H), 7.64 (d, J=8.1 Hz, 2H), 7.45 (dd,J=8.2, 1.7 Hz, 1H), 7.31 (d, J=8.8 Hz, 1H), 7.19 (d, J=2.6 Hz, 1H),7.05-6.97 (m, 1H), 6.93 (d, J=1.7 Hz, 1H), 3.77 (s, 3H) ppm.

Step 4:4-[[4-(3-furyl)-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(154)

A solution of4-[[4-bromo-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(30 mg, 0.05701 mmol),2-(2,5-dihydrofuran-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (17mg, 0.08671 mmol), Pd(dppf)₂Cl₂ (5 mg, 0.006123 mmol), K₂CO₃ (15 mg,0.1085 mmol) in dioxane (500 μL)/water (50 μL) was flushed with N₂ andheated at 100° C. for 16 h. The reaction mixture was purified by reversephase HPLC (gradient of 10-99% acetonitrile in water containing HCl as amodifier) to give4-[[4-(3-furyl)-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(1.0 mg, 3%), ESI-MS m/z calc. 513.11475, found 514.2 (M+1)⁺; Retentiontime (Method B): 1.75 minutes.

The compounds set forth in Table 15 were prepared by methods analogousto the preparation of compound 154 and Example 22.

TABLE 15 Additional Compounds Prepared By Methods Analogous to Example22. Cmpd No. Compound Name LC/MS NMR (shifts in ppm) 1554-[[4-(4-chlorophenyl)- ESI-MS m/z 1H NMR (400 MHz, DMSO-d6) ä 10.88 (s,2-[2-methoxy-4- calc. 557.09656, 1H), 8.51 (d, J = 5.5 Hz, 1H), 8.31 (d,J = 2.2 (trifluoromethoxy)phe- found 558.3 Hz, 1H), 8.11-8.06 (m, 1H),7.86 (dd, J = noxy]benzoyl]amino]pyr- (M + 1)+; 5.6, 2.2 Hz, 1H), 7.79(d, J = 8.0 Hz, 1H), idine-2-carboxamide Retention time 7.68-7.60 (m,3H), 7.60-7.49 (m, 3H), 7.23 (Method B): (d, J = 8.8 Hz, 1H), 7.15 (d, J= 2.7 Hz, 1H), 1.48 minutes 7.10 (d, J = 1.6 Hz, 1H), 6.97 (d, J = 9.1Hz, 1H), 3.77 (s, 3H). 156 4-[[4-(4-fluorophenyl)- ESI-MS m/z ¹H NMR(400 MHz, DMSO-d₆) δ 10.89 (s, 2-[2-methoxy-4- calc. 541.1261, 1H), 8.51(d, J = 5.5 Hz, 1H), 8.31 (s, 1H), (trifluoromethoxy)phe- found 542.18.10 (s, 1H), 7.91-7.83 (m, 1H), 7.78 (d, J = noxy]benzoyl]amino]pyr-(M + 1)+; 7.9 Hz, 1H), 7.72-7.60 (m, 3H), 7.56 (d, idine-2-carboxamideRetention time J = 7.9 Hz, 1H), 7.30 (t, J = 8.6 Hz, 2H), 7.23 (MethodB): (d, J = 8.8 Hz, 1H), 7.15 (d, J = 2.6 Hz, 1H), 1.32 minutes 7.08 (s,1H), 6.98 (d, 1H), 3.77 (s, 3H). 157 4-[[2-[2-methoxy-4- ESI-MS m/z ¹HNMR (400 MHz, DMSO-d₆) δ 10.94 (s, (trifluoromethoxy)phe- calc.591.12286, 1H), 8.52 (d, J = 5.5 Hz, 1H), 8.32 (d, J = 2.1 noxy]-4-[4-found 592.2 Hz, 1H), 8.10 (s, 1H), 7.93-7.75 (m, 6H),(trifluoromethyl)phenyl] (M + 1)+; 7.71-7.57 (m, 2H), 7.25 (d, J = 8.8Hz, 1H), benzoyl]amino]pyridine- Retention time 7.21-7.09 (m, 2H), 6.98(d, 1H), 3.77 (s, 2-carboxamide (Method B): 3H). 1.51 minutes

Example 234-[[2-(4-fluoro-2-methoxy-phenoxy)-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(159)

Step 1:4-[[2-bromo-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide

To a solution of 2-bromo-4-(trifluoromethyl)benzoic acid (5.0 g, 18.59mmol) in DMF (135 μL, 1.744 mmol), and DCM (50 mL) at 0° C. was addedoxalyl chloride (7.6 mL, 87.12 mmol) dropwise over 3 minutes. Themixture was stirred at RT for 2 h then concentrated in vacuo. Theintermediate was taken up in DCM (5 mL) and added drop-wise to asolution of 4-aminopyridine-2-carboxamide (2.4 g, 17.50 mmol), DIEA (3.0mL, 17.22 mmol), and DCM (25 mL) at 0° C. The reaction mixture wasstirred at RT for 2 h. The reaction mixture concentrated under vacuo andpurified by silica gel column chromatography using a MeOH/DCM eluent.The resultant material was triturated with diethyl ether (100 mL) andfiltered to give4-[[2-bromo-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide (1.2g, 17%) as a white solid. ¹H NMR (500 MHz, DMSO-d6) δ 11.23 (s, 1H),8.57 (d, J=5.5 Hz, 1H), 8.38 (d, J=2.3 Hz, 1H), 8.19 (d, J=1.7 Hz, 1H),8.17-8.09 (m, 1H), 7.98-7.82 (m, 3H), 7.69 (d, J=2.8 Hz, 1H) ppm.

Step 2:4-[[2-(4-fluoro-2-methoxy-phenoxy)-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(159)

A mixture of4-[[2-bromo-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide (25mg, 0.06441 mmol), 4-fluoro-2-methoxy-phenol (9.154 mg, 7.341 μL,0.06441 mmol), Cs₂CO₃ (20.99 mg, 0.06441 mmol), CuI (3.679 mg, 0.01932mmol), CsF (48.91 mg, 11.89 μL, 0.3220 mmol), and DMF (500.0 μL), washeated at 150° C. for 1 h. The crude was then purified by reverse phaseHPLC (gradient of 10-99% acetonitrile in water containing HCl as amodifier) to give4-[[2-(4-fluoro-2-methoxy-phenoxy)-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(8.0 mg, 25%) as a white solid. ESI-MS m/z calc. 449.09988, found 450.3(M+1)⁺; Retention time (Method B): 1.63 minutes. ¹H NMR (400 MHz,DMSO-d₆) δ 11.08 (s, 1H), 8.54 (d, J=5.5 Hz, 1H), 8.35 (d, J=2.1 Hz,1H), 8.12 (d, J=2.8 Hz, 1H), 7.88 (t, J=6.1 Hz, 2H), 7.67 (d, J=2.9 Hz,1H), 7.57 (d, J=8.0 Hz, 1H), 7.32 (dd, J=8.9, 5.8 Hz, 1H), 7.16 (ddd,J=10.6, 7.6, 2.9 Hz, 1H), 6.91-6.83 (m, 2H), 3.74 (s, 3H) ppm.

The compounds set forth in Table 16 were prepared by methods analogousto the preparation of compound 159 and Example 23.

TABLE 16 Additional Compounds Prepared By Methods Analogous to Example23. Cmpd No. Compound Name LC/MS NMR (shifts in ppm) 1604-[[2-(3-fluoro-4- ESI-MS m/z isopropoxy-phenoxy)- calc. 477.13116, 4-found 478.33 (trifluoromethyl)benzo- (M + 1)+; yl]amino]pyridine-2-Retention time carboxamide (Method B): 1.59 minutes 1614-[[2-(2-chloro-4- ESI-MS m/z ¹H NMR (400 MHz, DMSO-d₆) δ 11.23 (s,fluoro-phenoxy)-4- calc. 453.05032, 1H), 8.55 (d, J = 5.6 Hz, 1H), 8.34(d, J = 2.1 (trifluoromethyl)benzo- found 454.25 Hz, 1H), 8.18 (s, 1H),7.93 (d, J = 7.9 Hz, yl]amino]pyridine-2- (M + 1)+; 1H), 7.86 (dd, J =5.6, 2.2 Hz, 1H), 7.71 (d, J = carboxamide Retention time 8.3 Hz, 2H),7.50 (q, J = 9.5 Hz, 1H), 7.40- (Method B): 7.32 (m, 2H), 7.01 (d, J =9.6 Hz, 1H). 1.65 minutes 162 4-[[2-(5-chloro-2- ESI-MS m/z ¹H NMR (400MHz, DMSO-d₆) δ 11.10 (s, methoxy-phenoxy)-4- calc. 465.0703, 1H), 8.53(d, J = 5.5 Hz, 1H), 8.32 (d, J = 2.1 (trifluoromethyl)benzo- found466.29 Hz, 1H), 8.11 (d, J = 2.9 Hz, 1H), 7.91- yl]amino]pyridine-2-(M + 1)+; 7.81 (m, 2H), 7.67 (d, J = 2.9 Hz, 1H), 7.63- carboxamideRetention time 7.56 (m, 1H), 7.12 (d, J = 9.0 Hz, 2H), 7.05 (Method B):(s, 1H), 6.97 (d, J = 9.0 Hz, 2H), 4.57 (p, J = 1.59 minutes 6.0 Hz,1H), 1.24 (d, J = 6.0 Hz, 6H). 163 4-[[2-(3,4- ESI-MS m/z ¹H NMR (400MHz, DMSO-d₆) δ 11.11 (s, difluorophenoxy)-4- calc. 437.0799, 1H), 8.54(d, J = 5.5 Hz, 1H), 8.33 (d, J = 2.1 (trifluoromethyl)benzo- found438.29 Hz, 1H), 8.12 (d, J = 2.8 Hz, 1H), 7.90- yl]amino]pyridine-2-(M + 1)+; 7.82 (m, 2H), 7.67 (s, 1H), 7.60 (d, J = 8.0 carboxamideRetention time: Hz, 1H), 7.08 (dd, J = 9.0, 4.7 Hz, 1H), 7.03 1.62minutes (s, 1H), 6.75 (t, J = 8.6 Hz, 1H), 4.60 (t, J = 8.7 Hz, 2H),3.26 (t, J = 8.7 Hz, 2H). 164 4-[[2-(4- ESI-MS m/z ¹H NMR (400 MHz,DMSO-d₆) δ 11.15 (s, isopropoxyphenoxy)-4- calc. 459.1406, 1H), 8.54 (d,J = 5.5 Hz, 1H), 8.32 (d, J = 2.1 (trifluoromethyl)benzo- found 460.34Hz, 1H), 8.14 (s, 1H), 7.90 (d, J = 7.9 Hz, yl]amino]pyridine-2- (M +1)+; 1H), 7.85 (dd, J = 5.5, 2.2 Hz, 1H), 7.70 (s, carboxamide Retentiontime 1H), 7.65 (d, J = 8.1 Hz, 1H), 7.24-7.15 (m, (Method B): 2H), 7.12(dd, J = 6.5, 3.0 Hz, 1H), 7.01 (dt, 1.74 minutes J = 8.3, 3.7 Hz, 1H),2.20 (d, J = 1.9 Hz, 3H). 165 4-[[2-[(4-fluoro-2,3- ESI-MS m/z ¹H NMR(400 MHz, DMSO-d₆) δ 11.16 (s, dihydrobenzofuran-7- calc. 461.09988,1H), 8.54 (d, J = 5.5 Hz, 1H), 8.34 (d, J = 2.1 yl)oxy]-4- found 462.3Hz, 1H), 8.13 (d, J = 2.7 Hz, 1H), 7.91 (d, J = (trifluoromethyl)benzo-(M + 1)+; 7.9 Hz, 1H), 7.86 (dd, J = 5.6, 2.2 Hz, 1H),yl]amino]pyridine-2- Retention time 7.72-7.67 (m, 1H), 7.64 (d, J = 7.8Hz, 1H), carboxamide (Method B): 7.27 (dd, J = 11.2, 8.9 Hz, 1H),7.21-7.15 1.63 minutes (m, 1H), 7.06 (dd, J = 7.3, 2.8 Hz, 1H), 6.70(dt, J = 8.9, 3.1 Hz, 1H), 3.79 (s, 3H). 166 4-[[2-(4-fluoro-3- ESI-MSm/z ¹H NMR (400 MHz, DMSO-d₆) δ 11.23 (s, methyl-phenoxy)-4- calc.433.10495, 1H), 8.55 (d, J = 5.6 Hz, 1H), 8.34 (d, J = 2.1(trifluoromethyl)benzo- found 434.3 Hz, 1H), 8.18 (s, 1H), 7.93 (d, J =7.9 Hz, yl]amino]pyridine-2- (M + 1)+; 1H), 7.86 (dd, J = 5.6, 2.2 Hz,1H), 7.71 (d, J = carboxamide Retention time 8.3 Hz, 2H), 7.50 (q, J =9.5 Hz, 1H), 7.40- (Method B): 7.32 (m, 2H), 7.01 (d, J = 9.6 Hz, 1H).1.68 minutes 167 4-[[2-(4-fluoro-3- ESI-MS m/z ¹H NMR (400 MHz, DMSO-d₆)δ 11.10 (s, methoxy-phenoxy)-4- calc. 449.09988, 1H), 8.53 (d, J = 5.5Hz, 1H), 8.32 (d, J = 2.1 (trifluoromethyl)benzo- found 450.3 Hz, 1H),8.11 (d, J = 2.9 Hz, 1H), 7.91- yl]amino]pyridine-2- (M + 1)+; 7.81 (m,2H), 7.67 (d, J = 2.9 Hz, 1H), 7.63- carboxamide Retention time 7.56 (m,1H), 7.12 (d, J = 9.0 Hz, 2H), 7.05 (Method B): (s, 1H), 6.97 (d, J =9.0 Hz, 2H), 4.57 (p, J = 1.59 minutes 6.0 Hz, 1H), 1.24 (d, J = 6.0 Hz,6H).

Example 244-[[2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-[4-(trifluoromethyl)cyclohexyl]benzoyl]amino]pyridine-2-carboxamide(two diastereoisomers) (168)

Step 1:4-[[2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-[4-(trifluoromethyl)cyclohexen-1-yl]benzoyl]amino]pyridine-2-carboxamide

A solution of4-[[4-bromo-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(25 mg, 0.046 mmol),4,4,5,5-tetramethyl-2-[4-(trifluoromethyl)cyclohexen-1-yl]-1,3,2-dioxaborolane(25 mg, 0.092 mmol), K₂CO₃ (13 mg, 0.092 mmol), Pd(dppf)₂Cl₂ (7.5 mg,0.0092 mmol), in dioxane (0.5 mL) and water (50 μL) was heated at 100°C. for 16 h. The reaction mixture was purified by reverse phase HPLC(gradient of 10-99% acetonitrile in water containing HCl as a modifier)to give4-[[2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-[4-(trifluoromethyl)cyclohexen-1-yl]benzoyl]amino]pyridine-2-carboxamide(21.3 mg, 76%). ESI-MS m/z calc. 613.1448, found 614.3 (M+1)⁺; Retentiontime (Method B): 2.01 minutes. ¹H NMR (400 MHz, DMSO-d6) δ 11.22 (s,1H), 8.52 (d, J=5.5 Hz, 1H), 8.29 (d, J=2.2 Hz, 1H), 8.09 (d, J=2.9 Hz,1H), 7.81 (dd, J=5.5, 2.2 Hz, 1H), 7.64 (d, J=2.9 Hz, 1H), 7.24-7.14 (m,3H), 6.97 (dd, J=9.2, 2.3 Hz, 1H), 6.61 (s, 1H), 6.17 (s, 1H), 3.77 (s,3H), 2.40 (d, J=7.3 Hz, 3H), 2.28-2.09 (m, 2H), 2.03 (d, J=12.4 Hz, 1H),1.55 (td, J=12.4, 6.0 Hz, 1H) ppm.

Step 2:4-[[2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-[4-(trifluoromethyl)cyclohexyl]benzoyl]amino]pyridine-2-carboxamide(two diastereoisomers) (168)

A solution of4-[[2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-[4-(trifluoromethyl)cyclohexen-1-yl]benzoyl]amino]pyridine-2-carboxamide(15 mg, 0.02445 mmol) in EtOAc (250 μL)/MeOH (250 μL) was treated withPd/C (1 mg, 0.009397 mmol). The mixture was degassed with a flow of N₂(g) for 2 minutes, then purged with H₂ (balloon). The reaction wasstirred at RT for 16 h. The mixture was purified by reverse phase HPLCMethod B, resulting in two diastereoisomers. It is appreciated that bothdiastereomers of4-[[2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-[4-(trifluoromethyl)cyclohexyl]benzoyl]amino]pyridine-2-carboxamide(168) were isolated and that those diastereomers have the structure ofcompounds 168-a and 168-b (above). However, the relative stereochemistryof diastereomers 1 and 2 was not determined.

Diastereomer 1:4-[[2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-[4-(trifluoromethyl)cyclohexyl]benzoyl]amino]pyridine-2-carboxamide(4.1 mg, 71%). ESI-MS m/z calc. 615.1604, found 616.2 (M+1)⁺; Retentiontime (Method B): 1.97 minutes. ¹H NMR (400 MHz, DMSO-d₆) δ 11.27 (s,1H), 8.52 (d, J=5.5 Hz, 1H), 8.32 (d, J=2.1 Hz, 1H), 8.12 (s, 1H), 7.83(dd, J=5.5, 2.2 Hz, 1H), 7.67 (s, 1H), 7.24 (d, J=8.8 Hz, 1H), 7.19 (d,J=2.7 Hz, 1H), 7.05-6.95 (m, 2H), 6.43 (s, 1H), 3.76 (s, 3H), 2.82-2.72(m, 1H), 2.46 (m, 1H, obscured by DMSO), 1.75-1.55 (m, 8H) ppm.

Diastereomer 2:4-[[2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-[4-(trifluoromethyl)cyclohexyl]benzoyl]amino]pyridine-2-carboxamide(1.7 mg, 29%), ESI-MS m/z calc. 615.1604, found 616.3 (M+1)⁺; Retentiontime (Method B): 2.03 minutes respectively.

The compounds set forth in Table 17 were prepared by methods analogousto the preparation of compound 168. It is appreciated that bothdiastereomers of4-[[4-(4-tert-butylcyclohexyl)-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(169) were isolated and that those diastereomers have the structure ofcompounds 169-a and 169-b (see Table A, above). However, the relativestereochemistry of the first and second eluting diastereomers was notdetermined.

TABLE 17 Additional Compounds Prepared By Methods Analogous to Example24. Cmpd No. Compound Name LC/MS NMR (shifts in ppm) 169 4-[[4-(4-tert-%), ESI-MS m/z (first butylcyclohexyl)-2-fluoro- calc. 603.23566,diastereomer) 6-[2-methoxy-4- found 604.6 (trifluoromethoxy)phenoxy](M + 1)+; benzoyl]amino]pyridine-2- Retention time: carboxamide (MethodB) 2.3 minutes 169 4-[[4-(4-tert- ESI-MS m/z ¹H NMR (400 MHz, DMSO-d₆) δ(second butylcyclohexyl)-2-fluoro- calc. 603.23566, 11.22 (s, 1H), 8.51(d, J = 5.5 Hz, diastereomer) 6-[2-methoxy-4- found 604.4 1H), 8.30 (d,J = 2.1 Hz, 1H), 8.10 (trifluoromethoxy)phenoxy] (M + 1)+; (d, J = 2.9Hz, 1H), 7.81 (dd, J = benzoyl]amino]pyridine-2- Retention time: 5.6,2.2 Hz, 1H), 7.65 (d, J = 2.8 carboxamide (Method B) Hz, 1H), 7.21 (d, J= 8.8 Hz, 1H), 2.37 minutes 7.18 (d, J = 2.8 Hz, 1H), 7.05-6.88 (m, 2H),6.44 (s, 1H), 3.76 (s, 3H), 2.48-2.38 (m, 1H), 1.85-1.71 (m, 4H),1.47-1.25 (m, 2H), 1.15- 0.96 (m, 3H), 0.83 (s, 9H).

Example 255-[[2-fluoro-4-(4-fluorophenyl)-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(170)

Step 1:2-fluoro-4-(4-fluorophenyl)-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoicacid

A solution of4-bromo-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoic acid(1.22 g, 2.870 mmol), (4-fluorophenyl)boronic acid (830 mg, 5.932 mmol),Pd(PPh₃)₄ (550 mg, 0.4760 mmol) and Na₂CO₃ (500 mg, 4.717 mmol) werecombined in DMF (30 mL) and H₂O (10 mL), then heated at 100° C. for 3 h.The reaction was poured carefully into 1N HCl (caution: gas evolution)then washed with DCM. The organic layer was dried over Na₂SO₄, filteredand concentrated in vacuo. Purification by silica gel columnchromatography using a EtOAc/hexanes eluent gave2-fluoro-4-(4-fluorophenyl)-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoicacid (970 mg, 77%). ESI-MS m/z calc. 440.06833, found 441.0 (M+1)⁺;Retention time (Method B): 1.99.

Step 2:2-fluoro-4-(4-fluorophenyl)-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoylchloride

To a solution of2-fluoro-4-(4-fluorophenyl)-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoicacid (500 mg, 1.136 mmol) and DMF (25 μL, 0.3229 mmol) in DCM (6 mL) at0° C. was added oxalyl chloride (800 μL, 9.171 mmol) dropwise under a N₂atmosphere. The ice bath was removed after 10 minutes and the reactionwas stirred at RT for 50 minutes. The mixture was concentrated in vacuoto afford the crude2-fluoro-4-(4-fluorophenyl)-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoylchloride (520 mg, 100%) which was taken on without further purification.

Step 3:5-[[2-fluoro-4-(4-fluorophenyl)-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(170)

To a solution of 5-aminopyridine-2-carboxamide (9.715 mg, 0.07084 mmol),DMF (3.983 mg, 4.219 μL, 0.05449 mmol) and NMP (400 μL) was added DIEA(21.13 mg, 28.48 μL, 0.1635 mmol) under a N₂ atmosphere and theresulting clear solution was cooled to 0° C. A solution of2-fluoro-4-(4-fluorophenyl)-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoylchloride (25 mg, 0.05449 mmol) in NMP (200 μL) was then added and thereaction was stirred at RT for 16 h. The mixture was purified by reversephase HPLC (gradient of 10-99% acetonitrile in water containing HCl as amodifier) to give5-[[2-fluoro-4-(4-fluorophenyl)-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(21.1 mg, 69%). ESI-MS m/z calc. 559.11664, found 559.91 (M+1)⁺;Retention time (Method B): 1.97 minutes. ¹H NMR (400 MHz, DMSO-d6) δ11.21 (s, 1H), 8.86 (d, J=2.4 Hz, 1H), 8.26 (dd, J=8.7, 2.4 Hz, 1H),8.05 (s, 1H), 8.03 (s, 1H), 7.67 (dd, J=8.6, 5.4 Hz, 2H), 7.56 (s, 1H),7.52-7.44 (m, 1H), 7.35-7.23 (m, 3H), 7.17 (d, J=2.7 Hz, 1H), 6.98 (d,J=8.8 Hz, 1H), 6.87 (s, 1H), 3.77 (s, 3H) ppm.

Example 264-[[4-(4-chlorophenyl)-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(171)

Step 1:4-[[4-(4-chlorophenyl)-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(171)

A solution of4-[[4-bromo-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(25 mg, 0.04593 mmol), (4-chlorophenyl)boronic acid (approximately 14.36mg, 0.09186 mmol), K₂CO₃ (12.70 mg, 0.09186 mmol), Pd(dppf)₂Cl₂ (7.502mg, 0.009186 mmol) in dioxane (500 μL) and water (50 μL) was flushedwith N₂ and heated at 100° C. for 16 h. The reaction mixture waspurified by reverse phase HPLC (gradient of 10-99% acetonitrile in watercontaining HCl as a modifier) giving4-[[4-(4-chlorophenyl)-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(14.6 mg, 55%). ESI-MS m/z calc. 575.0871, found 576.1 (M+1)⁺; Retentiontime (Method B): 1.97 minutes. ¹H NMR (400 MHz, DMSO-d₆) δ 11.33 (s,1H), 8.54 (d, J=5.4 Hz, 1H), 8.32 (d, J=2.0 Hz, 1H), 8.12 (d, J=2.7 Hz,1H), 7.86-7.81 (m, 1H), 7.65 (d, J=8.9 Hz, 3H), 7.57-7.48 (m, 3H), 7.28(d, J=8.8 Hz, 1H), 7.18 (d, J=2.6 Hz, 1H), 6.98 (d, J=8.8 Hz, 1H), 6.88(s, 1H), 3.78 (s, 3H) ppm.

The compounds set forth in Table 18 were prepared by methods analogousto the preparation of compound 171 and Example 26.

TABLE 18 Additional Compounds Prepared By Methods Analogous to Example26. Cmpd No. Compound Name LC/MS NMR (shifts in ppm) 172 4-[[4-(4-tert-ESI-MS m/z 1H NMR (400 MHz, DMSO-d6) ä 11.30 (s, 1H),butylphenyl)-2-fluoro-6- calc. 597.18866, 8.54 (d, J = 5.5 Hz, 1H), 8.32(d, J = 2.1 Hz, 1H), [2-methoxy-4- found 598.3 8.10 (d, J = 2.8 Hz, 1H),7.84 (dd, J = 5.5, 2.2 Hz, (trifluoromethoxy)phe- (M + 1)+; 1H), 7.65(d, J = 2.9 Hz, 1H), 7.56-7.40 (m, 5H), noxy]benzoyl]amino]pyridine-Retention time 7.29 (d, J = 8.8 Hz, 1H), 7.18 (d, J = 2.7 Hz, 1H),2-carboxamide (Method B): 7.02-6.95 (m, 1H), 6.80 (s, 1H), 3.78 (s, 3H),2.19 minutes 1.29 (s, 9H).

Example 27N-(2-carbamoyl-4-pyridyl)-3-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-2-carboxamide(173)

Step 1: methyl 3-fluoro-5-(trifluoromethyl)pyridine-2-carboxylate

Concentrated sulfuric acid (8 mL, 150.1 mmol) was added to a solution of3-fluoro-5-(trifluoromethyl)pyridine-2-carboxylic acid (10 g, 47.82mmol) in methanol (200 mL) and the resulting reaction was stirred at 65°C. for 19.5 h. The residue was taken up in ethyl acetate and water andthe layers were separated. The organic layer was washed with saturatedaqueous NaHCO₃ (×1) and brine (×1). The aqueous layer was extracted withEtOAc (×1) and the organic layer was washed with saturated aqueousNaHCO₃ (×1) and brine (×1). The combined organic layer was dried overNa₂SO₄ filtered and concentrated in vacuo to yield methyl3-fluoro-5-(trifluoromethyl)pyridine-2-carboxylate (8.2311 g, 77%) as acream colored solid. ESI-MS m/z calc. 223.02563, found 224.0 (M+1)⁺;Retention time (Method C): 1.46 minutes.

Step 3: methyl3-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-2-carboxylate

A solution of methyl 3-fluoro-5-(trifluoromethyl)pyridine-2-carboxylate(2 g, 8.964 mmol), 2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenol(2.06 g, 9.756 mmol), and Cs₂CO₃ (2.966 g, 9.103 mmol) in DMF (15 mL)was heated at 100° C. for 16 h. The reaction was diluted with EtOAc andwashed with water (×3) and brine (×1). The organic layer was dried overNa₂SO₄, filtered and the concentrated in vacuo to yield methyl3-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-2-carboxylate(3.44 g, 93%) as an orange viscous liquid. ESI-MS m/z calc. 414.07297,found 415.1 (M+1)⁺; Retention time (Method C): 2.71 minutes. ¹H NMR (400MHz, DMSO-d6) δ 8.77-8.70 (m, 1H), 7.61-7.53 (m, 1H), 7.31 (d, J=8.8 Hz,1H), 7.22 (d, J=2.8 Hz, 1H), 7.01-6.93 (m, 1H), 3.88 (s, 3H) ppm.

Step 4:3-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-2-carboxylicacid

A solution of methyl3-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-2-carboxylate(3.14 g, 7.580 mmol) in methanol (30 mL) was treated with aqueous NaOH(30 mL of 1 M, 30.00 mmol). The reaction was stirred at 60° C. for 2 h.The reaction was acidified to pH˜1 with concentrated HCl. The reactionwas diluted with water and extracted with EtOAc (×1). The organic layerwas washed with brine (×1), dried over Na₂SO₄, filtered and concentratedunder vacuo to yield3-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-2-carboxylicacid (2.9 g, 96%) as a cream colored solid. ESI-MS m/z calc. 400.0573,found 401.1 (M+1)⁺; Retention time (Method C): 2.39 minutes. ¹H NMR (400MHz, DMSO-d6) δ 13.89 (s, 1H), 8.83-8.66 (m, 1H), 7.55 (d, J=1.8 Hz,1H), 7.29-7.23 (m, 2H), 7.09-6.93 (m, 1H) ppm.

Step 5:3-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-2-carbonylchloride

To3-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-2-carboxylicacid (540 mg, 1.349 mmol) and DMF (15 μL, 0.1937 mmol) in DCM (4 mL) at0° C. was added oxalyl chloride (180 μL, 2.063 mmol) dropwise under a N₂atmosphere. The ice bath was removed after 10 minutes and the reactionwas stirred at RT for 30 minutes then at 50° C. for 2 h. The reactionmixture was concentrated in vacuo to afford3-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-2-carbonylchloride. The intermediate was used in the next step without furtherpurification.

Step 6:N-(2-carbamoyl-4-pyridyl)-3-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-2-carboxamide(173)

To 4-aminopyridine-2-carboxamide (23.59 mg, 0.1720 mmol) in NMP (500 μL)and DIEA (55.56 mg, 74.88 μL, 0.4299 mmol) at 0° C. was added a solutionof3-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-2-carbonylchloride (60 mg, 0.1433 mmol) in NMP (200 μL) slowly. The mixture wasstirred at RT for 16 h. The crude product was filtered and purified byreverse phase HPLC (gradient of 10-99% acetonitrile in water containingHCl as a modifier) to yieldN-(2-carbamoyl-4-pyridyl)-3-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-2-carboxamide(26.5 mg, 35%). ESI-MS m/z calc. 519.10565, found 519.9 (M+1)⁺;Retention time (Method B): 1.77 minutes. 1H NMR (400 MHz, DMSO-d6) δ11.31 (s, 1H), 8.85 (s, 1H), 8.55 (d, J=5.5 Hz, 1H), 8.40 (d, J=2.2 Hz,1H), 8.10 (s, 1H), 7.92-7.86 (m, 1H), 7.70-7.61 (m, 2H), 7.31 (d, J=8.8Hz, 1H), 7.22 (d, J=2.7 Hz, 1H), 7.03-6.99 (m, 1H) ppm.

The compounds set forth in Table 19 were prepared by methods analogousto the preparation of compound 173 and Example 27.

TABLE 19 Additional Compounds Prepared By Methods Analogous to Example27. Cmpd No. Compound Name LC/MS NMR (shifts in ppm) 174N-(6-carbamoyl-3-pyridyl)-3- ESI-MS m/z 1H NMR (400 MHz, DMSO-d6) δ[2-(trideuteriomethoxy)-4- calc. 519.10565, 11.26 (s, 1H), 8.95 (d, J =2.4 Hz, 1H), (trifluoromethoxy)phenoxy]- found 520.2 8.86 (d, J = 1.7Hz, 1H), 8.34 (dd, J = 5-(trifluoromethyl)pyridine-2- (M + 1)+; 8.6, 2.5Hz, 1H), 8.09-7.98 (m, 2H), carboxamide Retention time 7.69 (s, 1H),7.59 (s, 1H), 7.31 (d, J = (Method C): 8.8 Hz, 1H), 7.23 (d, J = 2.7 Hz,1H), 2.35 minutes 7.01 (d, J = 9.4 Hz, 1H).

Example 284-[[2-(4-fluoro-2-methoxy-phenyl)-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(175)

Step 1: methyl 2-bromo-4-(trifluoromethyl)benzoate

A solution of 2-bromo-4-(trifluoromethyl)benzoic acid (2 g, 7.435 mmol)and H₂SO₄ (1.094 g, 594.6 μL, 11.15 mmol) in MeOH (50 mL) was heated at65° C. overnight. The reaction mixture was cooled to RT and concentratedin vacuo. The residue was taken up in ethyl acetate (20 mL) and water(20 mL) and the layers separated. The aqueous layer was extractedfurther with ethyl acetate (2×20 mL) and the combined organic layerswashed with saturated aqueous NaHCO₃ (1×20 mL), dried over MgSO₄ andconcentrated in vacuo to afford the product as a colorless oil. ¹H NMR(500 MHz, Chloroform-d) δ 7.97-7.86 (m, 2H), 7.64 (ddt, J=8.0, 1.3, 0.7Hz, 1H), 3.99 (s, 3H) ppm.

Step 2: methyl 2-(4-fluoro-2-methoxy-phenyl)-4-(trifluoromethyl)benzoate

A mixture of methyl 2-bromo-4-(trifluoromethyl)benzoate (500 mg, 1.767mmol), (4-fluoro-2-methoxy-phenyl)boronic acid (450 mg, 2.648 mmol),K₂CO₃ (488 mg, 3.531 mmol), Pd(PPh₃)₄ (41 mg, 0.03548 mmol), DMF (4.5mL) and water (500 μL) was heated at 80° C. for 2 h. The solution wasconcentrated in vacuo and the residue was purified by silica gel columnchromatography using a EtOAc/hexanes eluent to give methyl2-(4-fluoro-2-methoxy-phenyl)-4-(trifluoromethyl)benzoate (510 mg, 88%)as a clear oil. ¹H NMR (400 MHz, DMSO-d6) δ 7.95 (d, J=8.1 Hz, 1H),7.90-7.78 (m, 1H), 7.64 (d, J=1.9 Hz, 1H), 7.35 (dd, J=8.4, 6.8 Hz, 1H),6.98 (dd, J=11.3, 2.5 Hz, 1H), 6.88 (td, J=8.5, 2.5 Hz, 1H), 3.68 (s,3H), 3.66 (s, 3H) ppm.

Step 3: 2-(4-fluoro-2-methoxy-phenyl)-4-(trifluoromethyl)benzoic acid

A mixture of methyl2-(4-fluoro-2-methoxy-phenyl)-4-(trifluoromethyl)benzoate (500 mg, 1.523mmol), NaOH (1.2 g, 30.00 mmol) in H₂O (2.5 mL), and THF (2.5 mL) washeated at 100° C. for 2 h. The reaction mixture was acidified to pH=2(1.0 N aqueous HCl) and partitioned between water (50 mL) and EtOAc (100mL). The reaction was concentrated in vacuo and the residue purified bysilica gel column chromatography using a EtOAc/hexanes eluent to give2-(4-fluoro-2-methoxy-phenyl)-4-(trifluoromethyl)benzoic acid (230 mg,48%) as a white solid. ¹H NMR (400 MHz, DMSO-d6) δ 12.97 (s, 1H), 7.95(d, J=8.1 Hz, 1H), 7.86-7.76 (m, 1H), 7.59 (d, J=1.9 Hz, 1H), 7.30 (dd,J=8.4, 6.8 Hz, 1H), 6.97 (dd, J=11.4, 2.5 Hz, 1H), 6.85 (td, J=8.5, 2.5Hz, 1H), 3.69 (s, 3H) ppm.

Step 4:4-[[2-(4-fluoro-2-methoxy-phenyl)-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(175)

To a solution of2-(4-fluoro-2-methoxy-phenyl)-4-(trifluoromethyl)benzoic acid (100 mg,0.3182 mmol), DMF (3 μL, 0.03874 mmol), and DCM (1 mL), at 0° C.(ice-bath), was added oxalyl chloride (55 μL, 0.6305 mmol) dropwise over3 minutes. The mixture was stirred at RT for 2 h then concentrated invacuo. The intermediate was dissolved in DCM (5 mL) and added drop-wiseto a solution of 4-aminopyridine-2-carboxamide (44 mg, 0.3208 mmol),DIEA (140 μL, 0.8038 mmol) in DCM (500 μL) at a 0° C. The reactionmixture was stirred at RT for 2 h. The reaction mixture was concentratedunder vacuo and the residue purified by silica gel column chromatographyusing a EtOAc/hexanes eluent. The resultant material was triturated withdiethyl ether (100 mL) and filtered to give4-[[2-(4-fluoro-2-methoxy-phenyl)-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(13.1 mg, 9%) as a white solid. ESI-MS m/z calc. 433.10495, found 434.0(M+1)⁺; Retention time (Method B): 1.31 minutes. ¹H NMR (400 MHz,DMSO-d6) δ 11.01 (s, 1H), 8.50 (d, J=5.6 Hz, 1H), 8.30 (d, J=2.2 Hz,1H), 8.16 (s, 1H), 7.90 (d, J=1.4 Hz, 2H), 7.79 (dd, J=5.7, 2.2 Hz, 1H),7.70 (d, J=7.3 Hz, 2H), 7.40 (dd, J=8.4, 6.7 Hz, 1H), 6.94-6.82 (m, 2H),3.54 (s, 3H) ppm.

Example 295-[[6-(2-chloro-4-fluoro-phenoxy)-2-fluoro-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(176)

Step 1:6-(2-chloro-4-fluoro-phenoxy)-2-fluoro-3-(trifluoromethyl)benzoic acid

A solution of 6-bromo-2-fluoro-3-(trifluoromethyl)benzoic acid (5 g,17.42 mmol), 2-chloro-4-fluoro-phenol (3.0 g, 20.47 mmol), Cs₂CO₃ (11.4g, 34.99 mmol) in toluene (100 mL) was degassed with N₂ for 10 minutes,then CuI (664 mg, 3.486 mmol) was added. The reaction was flushed withN₂ then heated at 100° C. with vigorous stirring for 1 h. The mixturewas allowed to cool then diluted with ethyl acetate and water. The waterlayer was acidified with HCl (26 mL of 1 M, 26.00 mmol) and the productextracted with ethyl acetate. The organic layer was concentrated undervacuo and the residue was purified by silica gel column chromatographyusing a MeOH/DCM eluent to provide6-(2-chloro-4-fluoro-phenoxy)-2-fluoro-3-(trifluoromethyl)benzoic acid(5.1 g, 80%) as a white solid. ESI-MS m/z calc. 351.99255, found 353.0(M+1)⁺; Retention time (Method B): 1.66 minutes. ¹H NMR (400 MHz,DMSO-d6) δ 14.19 (s, 1H), 7.89-7.58 (m, 2H), 7.59-7.22 (m, 2H), 6.69 (d,J=8.9 Hz, 1H) ppm.

Step 2:5-[[6-(2-chloro-4-fluoro-phenoxy)-2-fluoro-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(176)

A mixture of6-(2-chloro-4-fluoro-phenoxy)-2-fluoro-3-(trifluoromethyl)benzoic acid(50 mg, 0.1390 mmol), oxalyl chloride (17.64 mg, 12.12 μL, 0.1390 mmol),and DMF (0.2541 mg, 0.2692 μL, 0.003476 mmol) in DCM (285.9 μL) wasstirred under nitrogen at RT for 1 h. The reaction mixture wasconcentrated in vacuo. To the residue was added DCM (143.0 μL),5-aminopyridine-2-carboxamide (28.59 mg, 0.2085 mmol), and DIEA (26.95mg, 36.32 μL, 0.2085 mmol). The reaction mixture was stirred at RT for 1h. The crude mixture was purified by reverse phase HPLC (gradient of10-99% acetonitrile in water containing HCl as a modifier) to give amide5-[[6-(2-chloro-4-fluoro-phenoxy)-2-fluoro-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(8.7 mg, 9%) as a white solid. ESI-MS m/z calc. 471.04092, found 471.9(M+1)⁺; Retention time (Method B): 1.77 minutes. ¹H NMR (400 MHz,DMSO-d6) δ 11.42 (s, 1H), 8.87 (d, J=2.4 Hz, 1H), 8.31 (dd, J=8.6, 2.4Hz, 1H), 8.07 (d, J=8.6 Hz, 1H), 8.04 (d, J=2.7 Hz, 1H), 7.86 (t, J=8.6Hz, 1H), 7.70 (dd, J=8.3, 3.0 Hz, 1H), 7.64-7.54 (m, 1H), 7.50 (dd,J=9.1, 5.2 Hz, 1H), 7.38 (td, J=9.2, 8.7, 3.0 Hz, 1H), 6.76 (d, J=8.9Hz, 1H) ppm.

Example 304-[[2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-phenyl-benzoyl]amino]pyridine-2-carboxamide(177)

Step 1:3-chloro-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoic acid

A solution of 6-bromo-3-chloro-2-fluoro-benzoic acid (2 g, 7.891 mmol),2-methoxy-4-(trifluoromethoxy)phenol (1.66 g, 7.976 mmol), Cs₂CO₃ (2.69g, 8.256 mmol) in toluene (15 mL) was bubbled with N₂ for 10 minutes,then CuI (359.6 mg, 1.888 mmol) was added. The reaction was heated at100° C. with vigorous stirring for 3 h. The mixture was allowed to cool,then diluted with ethyl acetate and water (50 mL) and then acidifiedwith 1 M HCl. The two layers were separated and the aqueous layer wasextracted with EtOAc (×3). The combined organic layer was washed withwater (×2), brine (×1), dried over Na₂SO₄, filtered through a plug ofcelite and concentrated in vacuo. Purification by silica gel columnchromatography using a EtOAc/hexanes eluent followed by purification byreverse phase HPLC (gradient of 10-99% acetonitrile in water containingHCl as a modifier) to yield3-chloro-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoic acid(510.6 mg, 17%). ESI-MS m/z calc. 380.00748, found 381.1 (M+1)⁺;Retention time (Method B): 2.53 minutes. ¹H NMR (400 MHz, DMSO-d6) δ13.92 (s, 1H), 7.56 (t, J=8.8 Hz, 1H), 7.29-7.14 (m, 2H), 6.99 (dd,J=8.8, 2.5 Hz, 1H), 6.56 (d, J=9.0 Hz, 1H), 3.79 (s, 3H) ppm.

Step 2:4-[[3-chloro-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide

To 3-chloro-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoicacid (83.8 mg, 0.2201 mmol) and DMF (15 μL, 0.1937 mmol) in DCM (1 mL)at 0° C. was added oxalyl chloride (53 μL, 0.6076 mmol) dropwise under aN₂ atmosphere. The ice bath was removed after 10 minutes and thereaction was stirred at RT for 2.5 h. The reaction was concentrated invacuo to afford3-chloro-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoylchloride. The intermediate was taken onto the next step without furtherpurification.

To 4-aminopyridine-2-carboxamide (36.2 mg, 0.2640 mmol) in NMP (0.5 mL)and DIEA (115 μL, 0.6602 mmol) at 0° C. was added a solution of3-chloro-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoylchloride in NMP (0.2 mL) slowly. The mixture was stirred at RT for 1 h.The crude product was purified by reverse phase HPLC (gradient of 10-99%acetonitrile in water containing HCl as a modifier) to yield4-[[3-chloro-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(25.8 mg, 23%). ESI-MS m/z calc. 499.05582, found 500.0 (M+1)⁺;Retention time (Method A): 0.55 minutes.

Step 3:4-[[2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-phenyl-benzoyl]amino]pyridine-2-carboxamide(177)

A solution of4-[[3-chloro-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(26 mg, 0.05202 mmol), phenylboronic acid (19.5 mg, 0.1599 mmol),Pd(dppf)₂Cl₂ (4.1 mg, 0.005021 mmol) and K₂CO₃ (79 μL of 2 M, 0.1580mmol) in dioxane (500 μL) was heated in the microwave at 120° C. for 20minutes. Further Pd(dppf)₂Cl₂ (11 mg) and K₂CO₃ (79 μL of 2 M, 0.1580mmol) were added to the reaction which was heated at 130° C. for 40minutes in the microwave. Further Pd(dppf)₂Cl₂ (11 mg), K₂CO₃ (79 μL of2 M, 0.1580 mmol), and phenylboronic acid (19.5 mg, 0.1599 mmol) wereadded to the reaction mixture which was then heated in the microwave at130° C. for 40 minutes. The crude product was purified by reverse phaseHPLC (gradient of 10-99% acetonitrile in water containing HCl as amodifier) to yield4-[[2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-phenyl-benzoyl]amino]pyridine-2-carboxamide(2.8 mg, 10%). ESI-MS m/z calc. 541.1261, found 542.2 (M+1)⁺; Retentiontime (Method C): 2.61 minutes (5 minutes run). ¹H NMR (400 MHz, DMSO-d6)δ 11.40 (s, 1H), 8.54 (d, J=5.3 Hz, 1H), 8.35 (s, 1H), 8.12 (s, 1H),7.92-7.80 (m, 1H), 7.67 (s, 1H), 7.61-7.48 (m, 5H), 7.48-7.38 (m, 1H),7.32 (d, J=8.9 Hz, 1H), 7.23 (s, 1H), 7.03 (d, J=8.3 Hz, 1H), 6.64 (d,J=8.8 Hz, 1H), 3.80 (s, 3H) ppm.

Example 314-[[2-ethyl-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(178)

Step 1: 2-bromo-6-fluoro-4-(trifluoromethyl)benzoic acid

To a solution containing freshly distilled diisopropylamine (4 mL, 28.54mmol) was added n-butyl lithium in hexanes (11 mL of 2.5 M, 27.5 mmol)over 10 minutes at 0° C. The mixture was then stirred at thistemperature for 30 minutes, then cooled to −78° C., and stirred at thistemperature for 30 minutes. This solution was then transferred viacannula into a solution of 1-bromo-3-fluoro-5-(trifluoromethyl)benzene(5 g, 20.576 mmol) in THF (20 mL) at −78° C. The resulting pale ambersolution was transferred via cannula to crushed CO₂ and the resultinggolden solution was stirred gently for 18 h. The reaction was dilutedwith NaOH (0.1M, 200 mL), and washed with Et₂O (3×200 mL), the aqueousphase was acidified with HCl (3M, until pH=1), and was extracted withEt₂O (3×200 mL), dried over MgSO₄, filtered and concentrated underreduced pressure to provide 2-bromo-6-fluoro-4-(trifluoromethyl)benzoicacid (5.34 g, 90%). ESI-MS m/z calc. 285.92526, found 287.0 (M+1)⁺;Retention time: 4.4 minutes; LCMS Method: Merckmillipore ChromolithSpeedROD C18 column (50×4.6 mm) and a dual gradient run from 5-100%mobile phase B over 12 minutes. Mobile phase A=water (0.1% CF₃CO₂H).Mobile phase B=acetonitrile (0.1% CF₃CO₂H); LCMS Method Detail: null.

Step 2:4-[[2-bromo-6-fluoro-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide

To a solution of 2-bromo-6-fluoro-4-(trifluoromethyl)benzoic acid (50mg, 0.174 mmol) and 4-aminopyridine-2-carboxamide (24 mg, 0.175 mmol) inpyridine (1.5 mL) was added POCl3 (0.016 mL, 0.172 mmol) at −20° C. to−15° C. and stirred 30 min at this temperature. The reaction wasquenched by addition of water (1 mL), then extracted with EtOAc (2×10mL). The combined organic phases were washed with water (3×2 mL), brine,dried over MgSO₄, and concentrated under reduced pressure to give4-[[2-bromo-6-fluoro-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(70 mg, 99%). ESI-MS m/z calc. 404.9736, found 406.0 (M+1)⁺; Retentiontime: 3.78 minutes and used directly in the next step without furtherpurification.

Step 3:4-[[2-bromo-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide

A solution of4-[[2-bromo-6-fluoro-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(1.00 g, 2.46 mmol), 2-methoxy-4-(trifluoromethoxy)phenol (564 mg, 2.71mmol) and Cs₂CO₃ (1.60 g, 4.91 mmol) in NMP (15 mL) was heated at 95° C.for 2 h. The reaction mixture was partitioned between ethyl acetate andwater. The organic layer was separated and washed with water and brine.The organic layer was dried over MgSO₄, then purified by silica gelcolumn chromatography using a ethyl acetate-dichloromethane gradient togive4-[[2-bromo-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(690 mg, 47%). ESI-MS m/z calc. 593.0021, found 595.0 (M+1)⁺; Retentiontime (Method B): 1.68 minutes. ¹H NMR (400 MHz, DMSO-d6) δ 11.14 (s,1H), 8.44 (d, J=5.5 Hz, 1H), 8.05 (dd, J=13.5, 2.5 Hz, 2H), 7.93-7.81(m, 2H), 7.63 (d, J=2.8 Hz, 1H), 7.48 (dd, J=5.6, 2.2 Hz, 1H), 6.86 (d,J=2.5 Hz, 1H), 6.79 (d, J=8.8 Hz, 1H), 6.73 (d, J=8.6 Hz, 1H), 3.50 (s,3H) ppm.

Step 4:4-[[2-ethyl-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(178)

Diethylzinc (80 μL of 2 M, 0.1600 mmol) was added under nitrogen to asolution of4-[[2-bromo-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(48 mg, 0.08077 mmol) and Pd(dppf)Cl₂ (3.1 mg, 0.004237 mmol) in dioxane(0.6 mL) in a capped vial and the resulting pale yellow solution heatedat 100° C. for 1 h. Additional diethylzinc (80 μL of 2 M, 0.1600 mmol)was added and the solution heated at 100° C. for a further 1 h. Thereaction was quenched with MeOH (500 uL) and partitioned between ethylacetate and 1 M aqueous HCl. The organic layer was dried over Na₂SO₄,filtered and concentrated. HPLC purification (10-100% CH₃CN/5 mM HCl)gave partially purified product. The product fractions were concentratedto a cloudy white suspension with some solid precipitate. The cloudysolution was decanted from the white solid. The solid was dried undervacuum, then suspended in hexane and dissolved with the slow addition ofDCM. The DCM was slowly removed under rotary vacuum until a white solidbegan to precipitate. The precipitate was allowed to settle and themother liquor decanted. The isolated solid was dried under high vacuumto give4-[[2-ethyl-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(7.1 mg, 15%). ESI-MS m/z calc. 543.12286, found 544.6 (M+1)⁺; Retentiontime (Method B): 1.77 minutes. ¹H NMR (400 MHz, Methanol-d4) δ 8.42 (d,J=5.5 Hz, 1H), 8.01 (d, J=2.1 Hz, 1H), 7.80 (d, J=8.2 Hz, 1H), 7.63 (dd,J=5.5, 2.1 Hz, 1H), 7.39 (d, J=8.2 Hz, 1H), 6.69-6.55 (m, 3H), 3.47 (s,3H), 2.75 (q, J=7.6 Hz, 2H), 1.24 (t, J=7.6 Hz, 3H) ppm.

Example 325-[[6-(3,4-difluoro-2-methoxy-phenoxy)-2-methyl-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(179)

Step 1: 2-bromo-6-fluoro-3-(trifluoromethyl)benzoic acid

To a stirred solution of 2-bromo-4-fluoro-1-(trifluoromethyl)benzene(2.5 mL, 17 mmol) in anhydrous THF (150 mL) was added LDA (10 mL of 2.0M, 20 mmol) at −78° C. The reaction mixture was stirred at thistemperature for 2 h. The resulting yellow solution was then transferredvia cannula onto crushed CO₂ and the resulting emulsion was stirredgently for 17 h. The slurry was taken up 0.2 M NaOH solution (150 mL)and extracted with diethyl ether (200 mL). The aqueous layer wasacidified to pH=1 and then extracted with diethyl ether (3×250 mL). Thecombined organic layer was washed with brine (200 mL), dried overNa₂SO₄, filtered, and concentrated under reduced pressure to give2-bromo-6-fluoro-3-(trifluoromethyl)benzoic acid (4.62 g, 90%) as anoff-white solid. ESI-MS m/z calc. 285.9253, found 287.3 (M+1)⁺;Retention time (Method G): 2.53 minutes.

Step 2: tert-butyl 2-bromo-6-fluoro-3-(trifluoromethyl)benzoate

A solution of 2-bromo-6-fluoro-3-(trifluoromethyl)benzoic acid (8.0 g,27.87 mmol), tert-butoxycarbonyl tert-butyl carbonate (9.1 g, 41.70mmol), DMAP (680 mg, 5.566 mmol) and t-BuOH (8 mL) was heated at 90° C.for 1 h. The reaction mixture cooled to RT and directly purified bysilica gel column chromatography using a EtOAc/hexanes eluent to givetert-butyl 2-bromo-6-fluoro-3-(trifluoromethyl)benzoate (8.1 g, 85%) asa white solid. ESI-MS m/z calc. 341.98785, found 344.8 (M+1)⁺; Retentiontime (Method B): 2.02 minutes. ¹H NMR (400 MHz, DMSO-d6) δ 8.03 (dd,J=9.0, 5.7 Hz, 1H), 7.64 (t, J=8.6 Hz, 1H), 1.58 (s, 9H) ppm.

Step 3: tert-butyl2-bromo-6-(3,4-difluoro-2-methoxy-phenoxy)-3-(trifluoromethyl)benzoate

A solution of tert-butyl 2-bromo-6-fluoro-3-(trifluoromethyl)benzoate(1.0 g, 2.915 mmol), 3,4-difluoro-2-methoxy-phenol (700 mg, 4.372 mmol),K₂CO₃ (806 mg, 5.832 mmol), in DMF (3 mL) was purged with nitrogen andheated at 100° C. for 1 h. The reaction mixture was cooled to RT andthen directly purified by silica gel column chromatography using aEtOAc/hexanes eluent. to give tert-butyl2-bromo-6-(3,4-difluoro-2-methoxy-phenoxy)-3-(trifluoromethyl)benzoate(1.3 g, 92%) as a clear oil. ¹H NMR (400 MHz, DMSO-d6) δ 7.80 (d, J=8.9Hz, 1H), 7.29 (q, J=9.3 Hz, 1H), 7.20-7.05 (m, 1H), 6.92 (d, J=8.9 Hz,1H), 3.86 (s, 3H), 1.55 (s, 9H) ppm.

Step 4: tert-butyl6-(3,4-difluoro-2-methoxy-phenoxy)-2-methyl-3-(trifluoromethyl)benzoate

A solution of tert-butyl2-bromo-6-(3,4-difluoro-2-methoxy-phenoxy)-3-(trifluoromethyl)benzoate(1.3 g, 2.690 mmol), methylboronic acid (829 mg, 13.85 mmol),Pd(dppf)₂Cl₂ (226 mg, 0.2767 mmol), and K₂CO₃ (1.1 g, 7.959 mmol) indioxane (6.0 mL) and water (600 μL) was heated at 120° C. for 30minutes. The reaction mixture was cooled to RT and then directlypurified by silica gel column chromatography using a EtOAc/hexaneseluent to give tert-butyl6-(3,4-difluoro-2-methoxy-phenoxy)-2-methyl-3-(trifluoromethyl)benzoate(1.0 g, 89%) as a clear oil. ¹H NMR (400 MHz, DMSO-d6) δ 7.67 (d, J=8.9Hz, 1H), 7.25 (q, J=9.3 Hz, 1H), 7.01 (ddd, J=9.3, 5.1, 2.2 Hz, 1H),6.74 (d, J=8.8 Hz, 1H), 3.86 (s, 3H), 2.40 (s, 3H), 1.53 (s, 9H) ppm.

Step 5:6-(3,4-difluoro-2-methoxy-phenoxy)-2-methyl-3-(trifluoromethyl)benzoicacid

A solution of tert-butyl6-(3,4-difluoro-2-methoxy-phenoxy)-2-methyl-3-(trifluoromethyl)benzoate(1.0 g, 2.390 mmol), TFA (27 mL, 350.5 mmol), water (1.7 mL, 94.36 mmol)and THF (5 mL) was stirred at RT for 1 h. The reaction was concentratedunder vacuo and purified by silica gel column chromatography using aEtOAc/hexanes eluent to give6-(3,4-difluoro-2-methoxy-phenoxy)-2-methyl-3-(trifluoromethyl)benzoicacid (390 mg, 45%) as a white solid. ¹H NMR (400 MHz, DMSO-d6) δ 13.75(s, 1H), 7.65 (d, J=8.8 Hz, 1H), 7.25 (q, J=9.3 Hz, 1H), 7.03 (ddd,J=9.5, 5.1, 2.2 Hz, 1H), 6.72 (d, J=8.9 Hz, 1H), 3.85 (s, 3H), 2.47-2.29(m, 3H) ppm.

Step 6:5-[[6-(3,4-difluoro-2-methoxy-phenoxy)-2-methyl-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(179)

To a solution of6-(3,4-difluoro-2-methoxy-phenoxy)-2-methyl-3-(trifluoromethyl)benzoicacid (50 mg, 0.1380 mmol) in DCM (750 μL) was added DMF (3 μL, 0.03874mmol) followed by the slow dropwise addition of oxalyl chloride (72 μL,0.8254 mmol). The reaction mixture was allowed to stir at RT for 30minutes then concentrated in vacuo. Additional DCM (1 mL) was added, andthe solution again concentrated in vacuo. The remaining residue wastaken up in NMP (300 μL) and added to a solution of5-aminopyridine-2-carboxamide (32 mg, 0.2333 mmol) and DIEA (120 μL,0.6889 mmol) in NMP (300 μL). The reaction mixture was allowed to stirat 75° C. overnight then purified by reverse phase HPLC (gradient of10-99% acetonitrile in water containing HCl as a modifier) to give5-[[6-(3,4-difluoro-2-methoxy-phenoxy)-2-methyl-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(18 mg, 24%) as a white solid. ESI-MS m/z calc. 481.1061, found 482.5(M+1)⁺; Retention time (Method I): 1.65 minutes. ¹H NMR (400 MHz,DMSO-d6) δ 11.23 (s, 1H), 8.89 (d, J=2.4 Hz, 1H), 8.35 (dd, J=8.6, 2.4Hz, 1H), 8.14-7.93 (m, 2H), 7.73 (d, J=8.9 Hz, 1H), 7.56 (s, 1H), 7.27(q, J=9.3 Hz, 1H), 7.09 (ddd, J=9.4, 5.1, 2.1 Hz, 1H), 6.77 (d, J=8.8Hz, 1H), 3.84 (s, 3H), 2.45 (s, 3H) ppm.

The compounds set forth in Table 20 were prepared by methods analogousto the preparation of compound 179.

TABLE 20 Additional Compounds Prepared By Methods Analogous to Example32. Cmpd No. Compound Name LC/MS NMR (shifts in ppm) 1804-[[6-(3,4-difluoro-2- ESI-MS m/z ¹H NMR (400 MHz, DMSO-d₆) δ 10.54methoxy-phenoxy)-2- calc. 495.12173, (s, 1H), 8.48 (d, J = 8.2 Hz, 2H),8.09 (s, methyl-3- found 496.2 1H), 7.72 (d, J = 8.9 Hz, 1H), 7.63 (s,1H), (trifluoromethyl)benzoyl]ami- (M + 1)+; 7.37-7.21 (m, 1H),7.21-6.98 (m, 1H), no]-5-methyl- Retention time 6.77 (d, J = 8.8 Hz,1H), 3.86 (s, 3H), 2.48 pyridine-2-carboxamide (Method B): (s, 3H,obscured by solvent peak), 2.31 (s, 1.65 minutes. 3H).

Example 334-[[3-cyclopropyl-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzoyl]amino]pyridine-2-carboxamide(181)

Step 1:3-bromo-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzaldehyde

To 3-bromo-6-fluoro-2-methyl-benzaldehyde (2400 mg, 11.06 mmol) and2-methoxy-4-(trifluoromethoxy)phenol (2.19 g, 10.52 mmol) inN,N-dimethylformamide (50 mL) was added Cs₂CO₃ (3.42 g, 10.50 mmol)under a N₂ atm. and the mixture was heated at 100° C. for 1.25 hours.After cooling to RT the mixture was diluted with ethyl acetate and washwith water, brine, dried over Na₂SO₄, and concentrated under reducedpressure. The residue was purified by column chromatography using agradient of ethyl acetate in hexanes (0-15%) to yield3-bromo-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzaldehyde(709 mg, 16%) as an off white solid. ¹H NMR (400 MHz, Chloroform-d) δ10.68 (s, 1H), 7.58 (d, J=8.9 Hz, 1H), 7.06 (d, J=8.4 Hz, 1H), 6.85 (d,J=9.5 Hz, 2H), 6.46 (d, J=8.9 Hz, 1H), 3.79 (s, 3H), 2.71 (s, 3H) ppm.ESI-MS m/z calc. 405.99, found 407.14 (M+1)⁺; Retention time (Method A):0.89 minutes.

Step 2:3-cyclopropyl-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzaldehyde

To a flask charged with3-bromo-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzaldehyde(80 mg, 0.197 mmol) and palladium tri-tert-butylphosphane (18 mg, 0.0352mmol), under an atmosphere of N₂ at 0° C. was added THF (1 mL) followedby bromo(cyclopropyl)zinc (600 μL of 0.5 M, 0.30 mmol) in THF and thereaction mixture was gradually warmed to room temperature over 1 h. Themixture as stirred at RT for 30 minutes. The reaction mixture wasquenched with 1N HCl, the aq. layer was extracted with DCM (3×). Thecombined organic layers were dried over Na₂SO₄, filtered andconcentrated. The residue was purified by column chromatography using agradient of ethyl acetate in hexanes (0-15%) to yield3-cyclopropyl-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzaldehyde(69 mg, 95%) as a white solid. ¹H NMR (400 MHz, Chloroform-d) δ 10.72(s, 1H), 7.16 (d, J=8.6 Hz, 1H), 6.95 (d, J=8.7 Hz, 1H), 6.85 (d, J=2.7Hz, 1H), 6.80 (d, J=8.9 Hz, 1H), 6.51 (d, J=8.6 Hz, 1H), 3.82 (s, 3H),2.72 (s, 3H), 1.86 (td, J=8.1, 4.1 Hz, 1H), 1.05-0.87 (m, 2H), 0.56 (h,J=4.3 Hz, 2H) ppm. ESI-MS m/z calc. 366.108, found 367.26 (M+1)⁺;Retention time (Method A): 0.85 minutes.

Step 3:3-cyclopropyl-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzoicacid

To a solution of3-cyclopropyl-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzaldehyde(69 mg, 0.188 mmol) in tert-butyl alcohol (1 mL), acetonitrile (0.6 mL),and water (0.6 mL) was added sodium dihydrogen phosphate (26 mg, 0.217mmol) and 2-methyl-2-butene (100 μL, 0.945 mmol) (cooled container inice prior to syringing out). To this mixture was added sodium chlorite(22 mg, 0.243 mmol) and the reaction was stirred at RT for 1.75 h. Themixture was diluted with 1 N HCl (15 mL) and extracted with ethylacetate (3×). The combined organics were dried over Na₂SO₄ andconcentrated under reduced pressure to give3-cyclopropyl-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzoicacid (71 mg, 94%). ¹H NMR (400 MHz, Chloroform-d) δ 7.06 (d, J=8.3 Hz,1H), 7.01 (d, J=8.6 Hz, 1H), 6.82 (d, J=9.0 Hz, 2H), 6.50 (d, J=8.6 Hz,1H), 3.81 (s, 3H), 2.53 (s, 3H), 1.83 (td, J=9.1, 8.2, 4.6 Hz, 1H),1.01-0.86 (m, 2H), 0.58 (t, J=5.2 Hz, 2H) ppm. ESI-MS m/z calc.382.1028, found 383.25 (M+1)⁺; Retention time (Method A): 0.74 minutes.

Step 4:4-[[3-cyclopropyl-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzoyl]amino]pyridine-2-carboxamide(181)

To a solution of3-cyclopropyl-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzoicacid (70 mg, 0.1831 mmol) in DCM (2 mL) cooled in an ice bath was addedDMF (2 μL, 0.0258 mmol) followed by the dropwise addition of oxalylchloride (32 μL, 0.367 mmol). The mixture was stirred at on ice for 10minutes and then at RT for 2 h. The reaction was concentrated underreduced pressure and flushed with N₂ to afford the acid chloride, whichwas taken directly into the next step.

A solution of methyl 4-aminopyridine-2-carboxylate (35 mg, 0.230 mmol)and DIEA (82 μL, 0.471 mmol) in DCM (2 mL) was cooled on ice and thecrude acid chloride in DCM (2 mL) was added dropwise. The ice bath wasremoved and the reaction mixture was stirred at RT overnight. Thereaction was quenched into water and extract with DCM (3×). The combinedorganics were dried over Na₂SO₄, and concentrated under reducedpressure. The major product was isolated by silica gel columnchromatography using a gradient of ethyl acetate in hexanes and was useddirectly in the next step. The isolated material was treated with NH₃(10 mL of 7 M, 70.00 mmol) in methanol for 28 hours. The solvent wasremoved under reduced pressure to give4-[[3-cyclopropyl-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzoyl]amino]pyridine-2-carboxamide(39 mg, 40%) as an off white solid. ¹H NMR (400 MHz, DMSO-d6) δ 11.05(s, 1H), 8.50 (d, J=5.5 Hz, 1H), 8.37 (d, J=2.1 Hz, 1H), 8.07 (d, J=3.1Hz, 1H), 7.84 (dd, J=5.5, 2.2 Hz, 1H), 7.62 (d, J=3.0 Hz, 1H), 7.18-7.07(m, 2H), 7.04 (d, J=8.7 Hz, 1H), 6.98-6.87 (m, 1H), 6.48 (d, J=8.6 Hz,1H), 3.74 (s, 3H), 2.37 (s, 3H), 1.90 (h, J=6.0 Hz, 1H), 1.00-0.85 (m,2H), 0.57 (h, J=4.0 Hz, 2H) ppm. ESI-MS m/z calc. 501.15115, found502.42 (M+1)⁺; Retention time (Method B): 1.87 minutes.

The compounds set forth in Table 21 were prepared by methods analogousto the preparation of compound 181.

TABLE 21 Additional Compounds Prepared By Methods Analogous to Example33. Cmpd No. Compound Name LC/MS NMR (shifts in ppm) 1825-[[3-cyclopropyl-6-[2- ESI-MS m/z 1H NMR (400 MHz, DMSO-d6) δmethoxy-4- calc. 501.15115, 10.95 (s, 1H), 8.87 (s, 1H), 8.30 (d, J =(trifluoromethoxy)phenoxy]- found 502.0 11.0 Hz, 1H), 8.10-7.90 (m, 2H),7.53 2-methyl- (M + 1)+; (s, 1H), 7.10 (d, J = 8.8 Hz, 2H), 7.04benzoyl]amino]pyridine-2- Retention time (d, J = 8.6 Hz, 1H), 6.94 (d, J= 8.8 Hz, carboxamide (Method B): 1H), 6.49 (d, J = 8.6 Hz, 1H), 3.74(s, 1.8 minutes 3H), 2.38 (s, 3H), 1.90 (s, 1H), 0.93 (d, J = 18.5 Hz,2H), 0.57 (d, J = 5.5 Hz, 2H).

Example 344-[[2-ethyl-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(183)

Step 1: tert-butyl2-bromo-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoate

K₂CO₃ (6.3 g, 45.58 mmol) was added to a completely soluble solution oftert-butyl 2-bromo-6-fluoro-3-(trifluoromethyl)benzoate (7.7 g, 22.44mmol) and 2-methoxy-4-(trifluoromethoxy)phenol (4.8 g, 23.06 mmol) inDMSO (27.0 mL). The mixture was heated at 100° C. for 1.25 hours andthen cooled to RT. To the mixture was added heptane (58 mL) and water(38 mL). The layers were separated and the organic layer was washed withwater, dried over MgSO4, concentrated under reduced pressure to givetert-butyl2-bromo-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoate(12.19 g, 102%). ¹H NMR (400 MHz, DMSO-d6) δ 7.79 (d, J=8.9 Hz, 1H),7.32-7.22 (m, 2H), 7.07-6.98 (m, 1H), 6.83 (d, J=8.9 Hz, 1H), 3.81 (s,3H), 1.53 (s, 9H) ppm.

Step 2: tert-butyl6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)-2-vinyl-benzoate

tert-Butyl2-bromo-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoate(1.00 g, 1.88 mmol) and vinylboronic acid (203 mg, 2.82 mmol) werecombined and dissolved in DMSO (10 mL). Aqueous potassium carbonate (2.8mL of 2 M, 5.600 mmol) was added followed by ferrous;cyclopenta-1,4-dien-1-yl(diphenyl)phosphane; dichloromethane;dichloropalladium (77 mg, 0.0943 mmol). The reaction mixture was stirredat 75° C. for 1 hour. The reaction mixture was diluted with EtOAc (75mL) and washed with water (1×75 mL) and brine (1×75 mL). The organiclayer was dried over sodium sulfate, filtered and concentrated underreduced pressure. The crude product was chromatographed on a silica gelcolumn eluting with a EtOAc/hexane gradient to give tert-butyl6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)-2-vinyl-benzoate(644 mg, 72%) as a clear colorless oil. ¹H NMR (400 MHz, DMSO-d6) δ 7.70(d, J=8.8 Hz, 1H), 7.26 (d, J=2.4 Hz, 1H), 7.19 (d, J=8.8 Hz, 1H), 7.00(d, J=9.7 Hz, 1H), 6.91-6.83 (m, 1H), 6.76 (d, J=8.8 Hz, 1H), 5.64 (d,J=11.6 Hz, 1H), 5.56 (d, J=17.6 Hz, 1H), 1.53 (s, 3H), 1.45 (s, 9H) ppm.ESI-MS m/z calc. 478.1215, found 423.1 (M−55)+; Retention time (MethodB): 2.37 minutes

Step 3: tert-butyl2-ethyl-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoate

tert-Butyl6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)-2-vinyl-benzoate(644 mg, 1.346 mmol) was dissolved in ethanol (15 mL) and the reactionwas flushed with N₂. Palladium (32 mg, 0.3007 mmol) (10 wt % on carbon,wet, degussa) was added. The reaction mixture was allowed to stir underan atmosphere of hydrogen gas overnight. The reaction mixture wasfiltered through celite, and the filtrate was concentrated under reducedpressure. The crude product was chromatographed on a silica gel columneluting with a 0-10% EtOAc/hexane gradient to give tert-butyl2-ethyl-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoate(522 mg, 81%) as a clear colorless oil. ESI-MS m/z calc. 480.13715,found 407.1 (M−73)+; Retention time (Method B): 2.46 minutes.

Step 4:2-ethyl-6-[2-methoxy-4-(trifluoromethoxy)phenoxyl-3-(trifluoromethyl)benzoicacid

tert-Butyl2-ethyl-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoate(544 mg, 1.132 mmol) was dissolved into a prepared solution of TFA (1mL, 12.98 mmol) in DCM (2 mL). The reaction mixture was allowed to stirat room temperature for 30 minutes. The reaction mixture was dilutedwith EtOAc (75 mL) and washed with water (1×75 mL) and brine (1×75 mL).The organic layer was dried over sodium sulfate, filtered andconcentrated under reduced pressure. The crude product was purified byreverse-phase HPLC eluting with a 35-99% acetonitrile/water (0.5 mMHC 1) gradient to give2-ethyl-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoicacid (297 mg, 62%) as a white sticky foam. ¹H NMR (400 MHz, DMSO-d6) δ13.67 (s, 1H), 7.64 (d, J=8.9 Hz, 1H), 7.25 (d, J=2.7 Hz, 1H), 7.21 (d,J=8.8 Hz, 1H), 7.05-6.97 (m, 1H), 6.60 (d, J=8.9 Hz, 1H), 3.80 (s, 3H),2.78 (q, J=7.5 Hz, 2H), 1.22 (t, J=7.5 Hz, 3H) ppm.

Step 5:4-[[2-ethyl-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(183)

2-Ethyl-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoicacid (43 mg, 0.101 mmol) was dissolved in dichloromethane (0.5 mL). DMF(approximately 0.37 mg, 0.39 μL, 0.0051 mmol) was added followed by theslow dropwise addition of oxalyl chloride (approximately 35 μL, 0.405mmol). The reaction mixture was allowed to stir at room temperature for1 hour. The reaction mixture was concentrated under reduced pressure.Additional dichloromethane (˜5 mL) was added, and the solution was againconcentrated to dryness. The remaining residue was taken up in NMP (0.5mL) and added to a mixture of 4-aminopyridine-2-carboxamide(approximately 21 mg, 0.152 mmol) and DIEA (approximately 106 μL, 0.608mmol). The reaction mixture was allowed to stir at 70° C. overnight. Theproduct was isolated by reverse-phase HPLC eluting with a 30-99%acetonitrile/water (5 mM HCl) gradient to give4-[[2-ethyl-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(16.3 mg, 28%). ¹H NMR (400 MHz, DMSO-d6) δ 11.28 (s, 1H), 8.54 (d,J=5.5 Hz, 1H), 8.39 (d, J=2.2 Hz, 1H), 8.16-8.07 (m, 1H), 7.86 (dd,J=5.6, 2.1 Hz, 1H), 7.72 (d, J=8.9 Hz, 1H), 7.66 (s, 1H), 7.32 (d, J=8.8Hz, 1H), 7.24 (d, J=2.6 Hz, 1H), 7.04 (d, J=9.1 Hz, 1H), 6.65 (d, J=8.9Hz, 1H), 3.78 (s, 3H), 2.81 (q, J=7.5 Hz, 2H), 1.23 (t, J=7.4 Hz, 3H)ppm. ESI-MS m/z calc. 543.12286, found 544.2 (M+1)⁺; Retention time(Method B): 1.88 minutes.

The compounds set forth in Table 22 were prepared by methods analogousto the preparation of compound 183.

TABLE 22 Additional Compounds Prepared By Methods Analogous to Example34. Cmpd No. Compound Name LC/MS NMR (shifts in ppm) 1845-[[2-ethyl-6-[2-methoxy- ESI-MS m/z 1H NMR (400 MHz, DMSO-d6) δ 11.16(s, 4- calc. 543.12286, 1H), 8.88 (d, J = 2.4 Hz, 1H), 8.34 (dd, J =(trifluoromethoxy)phenoxy]- found 544.2 8.6, 2.3 Hz, 1H), 8.05 (d, J =8.6 Hz, 1H), 3- (M + 1)+; 8.00 (s, 1H), 7.72 (d, J = 9.0 Hz, 1H), 7.59-(trifluoromethyl)benzoyl]ami- Retention time: 7.51 (m, 1H), 7.32 (d, J =8.8 Hz, 1H), 7.24 no]pyridine-2- 1.88 minutes (d, J = 2.7 Hz, 1H), 7.04(d, J = 8.4 Hz, 1H), carboxamide 6.66 (d, J = 8.9 Hz, 1H), 3.79 (s, 3H),2.82 (d, J = 7.9 Hz, 2H), 1.24 (t, J = 7.5 Hz, 3H).

Example 354-[[3-isobutyl-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzoyl]amino]pyridine-2-carboxamide(185)

Step 1:3-isobutyl-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzaldehyde

To a flask charged with3-bromo-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzaldehyde(250 mg, 0.617 mmol) and palladium tri-tert-butylphosphane (56 mg, 0.11mmol), under an atmosphere of N₂ at 0° C. was added THF (3 mL) followedby bromo(tert-butyl)zinc (1.9 mL of 0.5 M, 0.950 mmol) in THF and thereaction mixture was gradually warmed to room temperature over 1 h. Thereaction mixture was quenched with 1N HCl, the aq. layer was extractedwith DCM (3×). The combined organic layers were dried over Na₂SO₄,filtered and concentrated. The residue was purified by columnchromatography using a gradient of ethyl acetate in hexanes to yield3-isobutyl-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzaldehyde(65 mg, 22%). ¹H NMR (400 MHz, Chloroform-d) δ 10.73 (d, J=5.6 Hz, 1H),7.16 (d, J=8.5 Hz, 1H), 6.97 (d, J=8.7 Hz, 1H), 6.89-6.84 (m, 1H),6.84-6.78 (m, 1H), 6.53 (d, J=8.3 Hz, 1H), 3.82 (s, 3H), 2.55 (s, 3H),2.50 (d, J=7.8 Hz, 2H), 1.81 (hept, J=6.7 Hz, 1H), 0.91 (d, J=6.6 Hz,6H) ppm. ESI-MS m/z calc. 382.1392, found 383.29 (M+1)⁺; Retention time(Method A): 0.94 minutes.

Step 2:3-isobutyl-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzoicacid

To a solution of3-tert-butyl-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzaldehyde(60 mg, 0.126 mmol) in tert-butyl alcohol (1 mL), acetonitrile (0.5 mL),and water (0.5 mL) was added sodium dihydrogen phosphate (22 mg, 0.183mmol) and 2-methyl-2-butene (83 μL, 0.785 mmol). To this mixture wasadded sodium chlorite (19 mg, 0.210 mmol) and the reaction was stirredat RT for 1.75 h. The mixture was diluted with 1 N HCl (15 mL) andextracted with ethyl acetate (3×). The combined organics were dried overNa₂SO₄ and concentrated under reduced pressure to give3-isobutyl-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzoicacid (63 mg, 101%). ESI-MS m/z calc. 398.1341, found 399.29 (M+1)⁺;Retention time (Method A): 0.84 minutes.

Step 3:4-[[3-isobutyl-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzoyl]amino]pyridine-2-carboxamide(185)

To a solution of3-isobutyl-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzoicacid (60 mg, 0.121 mmol) in DCM (2 mL) cooled in an ice bath was addedDMF (2 μL, 0.02583 mmol) followed by the dropwise addition of oxalylchloride (26 μL, 0.298 mmol). The mixture was stirred on ice for 10 minsthen at RT for 1.5 h. The reaction was concentrated under reducedpressure and flushed with N₂ to afford the acid chloride, which wastaken directly into the next step.

A solution of methyl 4-aminopyridine-2-carboxylate (46 mg, 0.302 mmol)and DIEA (67 μL, 0.385 mmol) in DCM (2 mL) was cooled on ice and thecrude acid chloride in DCM (2 mL) was added dropwise. The ice bath wasremoved and the reaction mixture was stirred at RT overnight. Thereaction was quenched into water and extract with DCM (3×). The combinedorganics were dried over Na₂SO₄, and concentrated under reducedpressure. The residue was purified by silica gel column chromatographyusing a gradient of ethyl acetate in hexanes and was used directly inthe next step. The isolated material was treated with NH₃ (7 mL of 7 M,49.00 mmol) in methanol for 28 hours. The solvent was removed underreduced pressure and the residue as purified by medium pressure C18reverse phase chromatography (acetonitrile, water (5 mMHCl) gradient) togive4-[[3-isobutyl-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzoyl]amino]pyridine-2-carboxamide(6 mg, 10%). ¹H NMR (400 MHz, Chloroform-d) δ 9.55 (s, 1H), 9.08 (s,1H), 8.71 (s, 1H), 8.53 (d, J=5.5 Hz, 1H), 8.11 (s, 1H), 7.14 (d, J=8.4Hz, 1H), 7.09 (d, J=8.5 Hz, 1H), 6.88 (d, J=8.5 Hz, 2H), 6.52 (d, J=8.5Hz, 1H), 5.81 (s, 1H), 3.88 (s, 3H), 2.49 (d, J=7.1 Hz, 2H), 2.40 (s,3H), 1.83 (p, J=6.5 Hz, 1H), 0.92 (d, J=6.5 Hz, 6H) ppm. ESI-MS m/zcalc. 517.18243, found 518.45 (M+1)⁺; Retention time (Method B): 2.06minutes.

Example 364-[[2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-4-(trifluoromethyl)benzoyl]amino]-5-methyl-pyridine-2-carboxamide(186)

Step 1: tert-butyl 2-bromo-6-fluoro-4-(trifluoromethyl)benzoate

To a solution of 2-bromo-6-fluoro-4-(trifluoromethyl)benzoic acid (15 g,49.65 mmol) in tert-butanol (285 mL) was added DMAP (607 mg, 4.919 mmol)followed by tert-butoxycarbonyl tert-butyl carbonate (21.7 g, 96.45mmol) at room temperature. The reaction mixture was stirred at 40° C.overnight. The mixture was cooled to RT and concentrated under reducedpressure. The residue was triturated with 50 mL of hexanes and filtered.The filtrate was concentrated under reduced pressure to give tert-butyl2-bromo-6-fluoro-4-(trifluoromethyl)benzoate (14.94 g, 88%) as a paleyellow oil, which was used in next step without purification. ¹H NMR(400 MHz, DMSO-d6) δ 8.03 (s, 1H), 7.95 (d, J=9.0 Hz, 1H), 1.57 (s, 9H)ppm.

Step 2: tert-butyl2-bromo-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoate

A mixture of tert-butyl 2-bromo-6-fluoro-4-(trifluoromethyl)benzoate(2.97 g, 8.66 mmol), 2-methoxy-4-(trifluoromethoxy)phenol (2.4 g, 11.53mmol) and potassium carbonate (2.4 g, 17.37 mmol) in DMSO (12 mL) washeated at 100° C. for 1 h. The reaction mixture was allowed to cool toRT, was poured onto 50 mL of water and extracted with ethyl acetate(3×50 mL). The combined organic layers were washed with brine (50 mL),dried over sodium sulfate, filtered and concentrated under reducedpressure. The residue was purified by silica chromatography eluting withgradient of EtOAc and hexanes to give tert-butyl2-bromo-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoate(4.10 g, 89%). ¹H NMR (400 MHz, DMSO-d6) δ 7.85 (s, 1H), 7.25 (d, J=2.8Hz, 1H), 7.17 (d, J=8.8 Hz, 1H), 7.06 (s, 1H), 7.04-6.93 (m, 1H), 3.81(s, 3H), 1.48 (s, 9H) ppm.

Step 3: tert-butyl2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-4-(trifluoromethyl)benzoate

A mixture of tert-butyl2-bromo-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoate(1 g, 1.882 mmol), methylboronic acid (740 mg, 12.11 mmol), potassiumcarbonate (838 mg, 5.942 mmol) and ferrous;cyclopenta-1,4-dien-1-yl(diphenyl)phosphane dichloromethanedichloropalladium (154 mg, 0.1886 mmol) in dioxane (6 mL)/water (600 μL)was flushed with nitrogen, capped and heated at 120° C. for 30 minutesin an oil bath. The reaction mixture was allowed to cool to roomtemperature and was diluted with water (50 mL) and extracted with ethylacetate (3×50 mL). The combined organic layers were washed with brine,filtered, and concentrated reduced pressure. The residue was purified bysilica column chromatography eluting with a EtOAc/hexanes gradient togiving tert-butyl2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-4-(trifluoromethyl)benzoate(693 mg, 79%). ¹H NMR (400 MHz, DMSO-d6) δ 7.46 (s, 1H), 7.22 (d, J=2.6Hz, 1H), 7.04-6.89 (m, 3H), 3.81 (s, 3H), 2.38 (s, 3H), 1.43 (s, 9H)ppm.

Step 4:2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-4-(trifluoromethyl)benzoicacid

tert-Butyl2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-4-(trifluoromethyl)benzoate(693 mg, 1.49 mmol) was dissolved in a solution of TFA (2 mL, 25.96mmol) in DCM (6 mL). The mixture was stirred at room temperature for 16h. The mixture was concentrated under reduced pressure to give2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-4-(trifluoromethyl)benzoicacid (610 mg, 79%), which was used directly in the next step. ESI-MS m/zcalc. 410.0589, found 411.3 (M+1)⁺; Retention time (Method B): 1.87minutes.

Step 5:2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-4-(trifluoromethyl)benzoylchloride

To a solution of2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-4-(trifluoromethyl)benzoicacid (500 mg, 1.219 mmol), DMF (26 μL, 0.3358 mmol) and DCM (8 mL) at 0°C. under N₂ (g) was added oxalyl chloride (855 μL, 9.801 mmol). Thereaction was stirred at 0° C. for 10 min and then at RT for 1 h. Thereaction was concentrated under reduced pressure and the residue wasused directly in the next step.

Step 6: methyl4-[[2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-4-(trifluoromethyl)benzoyl]amino]-5-methyl-pyridine-2-carboxylate

In a vial was combined methyl 4-amino-5-methylpicolinate, DIEA (61 μL)and NMP (400 μL). The mixture was cooled in ice bath and a solution of2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-4-(trifluoromethyl)benzoylchloride (50 mg) in NMP (200 μL) was added drop wise. The resultingmixture was stirred at RT for 16 h. The reaction was purified directlyby reverse phase HPLC (C-18 Column and gradient system of 1-99% ACN/H2Owith 5 mM HCl modifier) giving methyl4-[[2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-4-(trifluoromethyl)benzoyl]amino]-5-methyl-pyridine-2-carboxylate(11 mg, 17%). ESI-MS m/z calc. 558.12256, found 559.3 (M+1)⁺; Retentiontime (Method B): 1.6 minutes. ¹H NMR (400 MHz, DMSO-d6) δ 10.48 (s, 1H),8.57 (d, J=7.2 Hz, 2H), 7.50 (d, J=1.6 Hz, 1H), 7.29-7.19 (m, 2H), 7.02(ddd, J=8.9, 2.8, 1.3 Hz, 1H), 6.78 (s, 1H), 3.89 (s, 3H), 3.79 (s, 3H),2.47 (s, 3H), 2.31 (s, 3H) ppm.

Step 7:4-[[2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-4-(trifluoromethyl)benzoyl]amino]-5-methyl-pyridine-2-carboxamide(186)

A vial containing methyl4-[[2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-4-(trifluoromethyl)benzoyl]amino]-5-methyl-pyridine-2-carboxylate(10 mg, 0.0179 mmol) was treated with ammonia in methanol (500 μL of 7M, 3.50 mmol). The solution was stirred at RT for 18 h. Solvent wasevaporated and the residue was purified by reverse phase LC-MS on C-18column with gradient of 1-99% ACN/H₂O (5 mM HCl) to give4-[[2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-4-(trifluoromethyl)benzoyl]amino]-5-methyl-pyridine-2-carboxamide(6.0 mg, 62%) as a white solid. ¹H NMR (400 MHz, DMSO-d6) δ 10.38 (s,1H), 8.46 (d, J=5.7 Hz, 2H), 8.07 (s, 1H), 7.61 (s, 1H), 7.50 (s, 1H),7.30-7.20 (m, 2H), 7.06-6.99 (m, 1H), 6.77 (s, 1H), 3.80 (s, 3H), 2.48(s, 3H), 2.29 (s, 3H) ppm. ESI-MS m/z calc. 543.12286, found 544.2(M+1)⁺; Retention time (Method B): 1.35 minutes.

The compounds set forth in Table 23 were prepared by methods analogousto the preparation of compound 186.

TABLE 23 Additional Compounds Prepared By Methods Analogous to Example36. Cmpd No. Compound Name LC/MS NMR (shifts in ppm) 1875-[[2-[2-methoxy-4- ESI-MS m/z 1H NMR (400 MHz, DMSO-d6) δ(trifluoromethoxy)phenoxy]- calc. 529.10724, 11.11 (s, 1H), 8.87 (s,1H), 8.29 (d, J = 6-methyl-4- found 530.2 9.0 Hz, 1H), 8.08-7.99 (m,2H), 7.55 (trifluoromethyl)benzoyl]ami- (M + 1)+; (s, 1H), 7.50 (s, 1H),7.25 (d, J = 8.8 no]pyridine-2-carboxamide Retention time Hz, 1H), 7.20(s, 1H), 7.01 (d, J = 8.8 (Method B): Hz, 1H), 6.79 (s, 1H), 3.76 (s,3H), 2.43 1.87 minutes (s, 3H). 188 4-[[2-[2-methoxy-4- ESI-MS m/z 1HNMR (400 MHz, DMSO-d6) δ (trifluoromethoxy)phenoxy]- calc. 529.10724,11.21 (s, 1H), 8.53 (d, J = 5.5 Hz, 1H), 6-methyl-4- found 530.2 8.35(d, J = 2.1 Hz, 1H), 8.10 (s, 1H), (trifluoromethyl)benzoyl]ami- (M +1)+; 7.83 (dd, J = 5.5, 2.2 Hz, 1H), 7.65 (s, no]pyridine-2-carboxamideRetention time 1H), 7.50 (s, 1H), 7.26 (d, J = 8.8 Hz, (Method B): 1H),7.20 (d, J = 2.7 Hz, 1H), 7.01 (d, 1.56 minutes J = 8.7 Hz, 1H), 6.77(s, 1H), 3.77 (s, 3H), 2.42 (s, 3H).

Example 374-[[2-(3,4-difluoro-2-methoxy-phenoxy)-6-methyl-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(189)

Step 1: tert-butyl2-bromo-6-(3,4-difluoro-2-methoxy-phenoxy)-4-(trifluoromethyl)benzoate

A mixture of tert-butyl 2-bromo-6-fluoro-4-(trifluoromethyl)benzoate (5g, 14.57 mmol), 3,4-difluoro-2-methoxy-phenol (3.03 g, 18.92 mmol) andpotassium carbonate (4.03 g, 29.16 mmol) in DMSO (20 mL) was heated at100° C. for 1 h. The reaction mixture was cooled to RT, poured onto 50mL of water and extracted with ethyl acetate (3×50 mL). The combinedorganic layers were washed with brine (50 mL), dried over sodiumsulfate, filtered and concentrated in under reduced pressure. Theresidue was purified by silica chromatography on eluting with gradientof EtOAc/hexanes to give tert-butyl2-bromo-6-(3,4-difluoro-2-methoxy-phenoxy)-4-(trifluoromethyl)benzoate(5.74 g, 82%) as an oil. ¹H NMR (400 MHz, DMSO-d6) δ 7.86 (s, 1H), 7.24(q, J=9.3 Hz, 1H), 7.16 (s, 1H), 7.02 (ddd, J=9.4, 5.1, 2.3 Hz, 1H),3.87 (s, 3H), 1.51 (s, 9H) ppm.

Step 2: tert-butyl2-(3,4-difluoro-2-methoxy-phenoxy)-6-methyl-4-(trifluoromethyl)benzoate

A mixture of tert-butyl2-bromo-6-(3,4-difluoro-2-methoxy-phenoxy)-4-(trifluoromethyl)benzoate(1 g, 2.069 mmol), methylboronic acid (815 mg, 13.34 mmol), potassiumcarbonate (921 mg, 6.53 mmol) and ferrous;cyclopenta-1,4-dien-1-yl(diphenyl)phosphane; dichloromethane;dichloropalladium (170 mg, 0.208 mmol) in dioxane (6 mL) and water (600μL) was flushed with nitrogen, capped and heated at 120° C. for 30minutes in oil bath. The reaction mixture was allowed to cool to roomtemperature and diluted with water (50 mL) and extracted with ethylacetate (2×50 mL). The combined organic layers were washed with brine,filtered, and concentrated under reduced pressure. The residue was thenpurified by silica column chromatography eluting with a EtOAc/hexanesgradient to give tert-butyl2-(3,4-difluoro-2-methoxy-phenoxy)-6-methyl-4-(trifluoromethyl)benzoate(388 mg, 45%) as clear colorless oil. ¹H NMR (400 MHz, DMSO-d6) δ 7.48(s, 1H), 7.21 (q, J=9.3 Hz, 1H), 6.96 (s, 1H), 6.93-6.84 (m, 1H), 3.87(s, 3H), 2.40 (d, J=3.7 Hz, 3H), 1.48 (s, 9H) ppm.

Step 3:2-(3,4-difluoro-2-methoxy-phenoxy)-6-methyl-4-(trifluoromethyl)benzoicacid

tert-butyl2-(3,4-difluoro-2-methoxy-phenoxy)-6-methyl-4-(trifluoromethyl)benzoate(388 mg, 0.93 mmol) was dissolved in a solution of TFA (2 mL, 25.96mmol) in DCM (6 mL). The mixture was stirred at RT for 16 h. The mixturewas concentrated under reduced pressure to give a thick oil. The oil wastiturated with hexanes to give2-(3,4-difluoro-2-methoxy-phenoxy)-6-methyl-4-(trifluoromethyl)benzoicacid (204 mg, 27%) as a white solid. ESI-MS m/z calc. 362.05774, found363.1 (M+1)⁺; Retention time (Method B): 1.78 minutes.

Step 4:4-[[2-(3,4-difluoro-2-methoxy-phenoxy)-6-methyl-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(189)

A solution of2-(3,4-difluoro-2-methoxy-phenoxy)-6-methyl-4-(trifluoromethyl)benzoicacid (25 mg, 0.06901 mmol) in DCM (75.00 μL) was treated with DMF(approximately 5 μL, 0.069 mmol), and the mixture was cooled in an icebath. To this solution was added oxalyl chloride (approximately 18 μL,0.207 mmol) dropwise. The resulting mixture was stirred in an ice bathfor 10 min, and then allowed to stir at RT for 1 h. The mixture wasconcentrated to dryness under vacuum to give a light yellow solid whichwas used directly in the next step.

The acid chloride intermediate was dissolved in NMP (300 μL) and addeddropwise to a cooled solution of 4-aminopyridine-2-carboxamide(approximately 19 mg, 0.138 mmol) and DIEA (approximately 36 μL, 0.207mmol) in NMP (250 μL). The reaction mixture was stirred at RT for 16 h.The mixture was filtered and purified by reverse phase HPLC on C-18column eluting with gradient 1-99% ACN/H₂O (5 mM HCl) to give4-[[2-(3,4-difluoro-2-methoxy-phenoxy)-6-methyl-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(17 mg, 50%) as a white solid. ESI-MS m/z calc. 481.1061, found 482.2(M+1)⁺; Retention time (Method B): 1.66 minutes. ¹H NMR (400 MHz,DMSO-d6) δ 11.26 (s, 1H), 8.54 (d, J=5.4 Hz, 1H), 8.36 (d, J=2.2 Hz,1H), 8.12-8.07 (m, 1H), 7.86-7.80 (m, 1H), 7.65 (s, 1H), 7.53 (s, 1H),7.24 (q, J=9.3 Hz, 1H), 7.03 (s, 1H), 6.93 (s, 1H), 3.82 (s, 3H), 2.43(s, 3H) ppm.

Example 385-[[6-(2-chloro-4-fluoro-phenoxy)-2-methyl-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(190)

Step 1: tert-butyl2-bromo-6-(2-chloro-4-fluoro-phenoxy)-3-(trifluoromethyl)benzoate

A stirring mixture of tert-butyl2-bromo-6-fluoro-3-(trifluoromethyl)benzoate (1.0 g, 2.91 mmol),2-chloro-4-fluoro-phenol (493 mg, 3.364 mmol), K₂CO₃ (800 mg, 5.788mmol), and DMSO (4 mL) was heated at 100° C. for 1 hour. The reactionmixture was cooled to RT and was then directly purified by silica gelcolumn chromatography using a gradient of EtOAc in hexanes to givetert-butyl2-bromo-6-(2-chloro-4-fluoro-phenoxy)-3-(trifluoromethyl)benzoate (1.3g, 95%) as a clear oil. ¹H NMR (400 MHz, DMSO-d6) δ 7.84 (d, J=8.9 Hz,1H), 7.72 (dd, J=8.4, 2.9 Hz, 1H), 7.52-7.23 (m, 2H), 6.92 (d, J=8.9 Hz,1H), 1.53 (s, 9H) ppm.

Step 2: tert-butyl6-(2-chloro-4-fluoro-phenoxy)-2-methyl-3-(trifluoromethyl)benzoate

To a stirring solution of tert-butyl2-bromo-6-(2-chloro-4-fluoro-phenoxy)-3-(trifluoromethyl)benzoate (800mg, 1.703 mmol), Pd(dppf)C₁₂ (16 mg, 0.02187 mmol), and 1,4-dioxane (8mL), under nitrogen, was added dimethylzinc (450 μL, 3.393 mmol). Thereaction mixture was heated at 100° C. for 2 hours. The cooled reactionwas directly purified by silica gel column chromatography using agradient of 1-100% EtOAc in hexanes to give tert-butyl6-(2-chloro-4-fluoro-phenoxy)-2-methyl-3-(trifluoromethyl)benzoate (450mg, 65%) as a clear oil. ¹H NMR (400 MHz, DMSO-d6) δ 7.76-7.64 (m, 2H),7.35-7.22 (m, 2H), 6.77 (d, J=8.8 Hz, 1H), 2.40 (s, 3H), 1.50 (s, 9H)ppm.

Step 3:6-(2-chloro-4-fluoro-phenoxy)-2-methyl-3-(trifluoromethyl)benzoic acid

A solution of tert-butyl6-(2-chloro-4-fluoro-phenoxy)-2-methyl-3-(trifluoromethyl)benzoate (400mg, 0.9882 mmol), TFA (11.4 mL, 148.0 mmol), water (700 μL, 38.86 mmol),and THF (400 μL), was stirred at room temperature for 1 hour. Thesolution was evaporated to dryness under reduced pressure and theresidue was diluted with DMSO (500 uL), filtered, and purified byreverse phase preparative chromatography using a C18 column and agradient eluent of 1 to 99% acetonitrile in water (5 mM HCl) to give6-(2-chloro-4-fluoro-phenoxy)-2-methyl-3-(trifluoromethyl)benzoic acid(180 mg, 34%) as a clear oil. ESI-MS m/z calc. 348.01764, found 351.0(M+1)⁺; Retention time (Method B): 1.87 minutes. ¹H NMR (400 MHz,DMSO-d6) δ 14.12-13.25 (m, 1H), 7.68 (dd, J=8.8, 5.7 Hz, 2H), 7.45-7.17(m, 2H), 6.66 (d, J=8.8 Hz, 1H), 2.41 (s, 3H) ppm.

Step 4:5-[[6-(2-chloro-4-fluoro-phenoxy)-2-methyl-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(190)

6-(2-Chloro-4-fluoro-phenoxy)-2-methyl-3-(trifluoromethyl)benzoic acid(25 mg, 0.0717 mmol) was dissolved in dichloromethane (375 μL). DMF (2μL, 0.0258 mmol) was added followed by the slow dropwise addition ofoxalyl chloride (40 μL, 0.4585 mmol). The reaction mixture was allowedto stir at room temperature for 30 minutes. The reaction mixture wasconcentrated under reduced pressure. Additional dichloromethane (˜1 mL)was added, and the solution was again concentrated to dryness. Theremaining residue was taken up in NMP (150 μL) and added to a preparedsolution of 5-aminopyridine-2-carboxamide (17 mg, 0.124 mmol) and DIEA(62 μL, 0.356 mmol) in NMP (150 μL). This reaction mixture was allowedto stir at 75° C. overnight. The reaction was diluted with DMSO (500uL), filtered, and purified by reverse phase preparative chromatographyusing a C18 column and a gradient eluent of 1 to 99% acetonitrile inwater (5 mM HCl) to give5-[[6-(2-chloro-4-fluoro-phenoxy)-2-methyl-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(16 mg, 47%) as a white solid. ESI-MS m/z calc. 467.06598, found 468.0(M+1)⁺; Retention time (Method B): 1.65 minutes. ¹H NMR (400 MHz,DMSO-d6) δ 11.19 (s, 1H), 8.88 (d, J=2.4 Hz, 1H), 8.33 (dd, J=8.6, 2.4Hz, 1H), 8.06 (d, J=8.6 Hz, 1H), 8.04-7.97 (m, 1H), 7.75 (d, J=8.9 Hz,1H), 7.67 (dd, J=8.4, 2.9 Hz, 1H), 7.61-7.49 (m, 1H), 7.41 (dd, J=9.1,5.3 Hz, 1H), 7.35 (td, J=8.5, 2.8 Hz, 1H), 6.72 (d, J=8.8 Hz, 1H), 2.46(s, 3H) ppm.

Example 394-[[2-chloro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(191)

Step 1:4-[[2-chloro-6-fluoro-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide

2-Chloro-6-fluoro-3-(trifluoromethyl)benzoic acid (900 mg, 3.710 mmol)was dissolved in dichloromethane (13 mL). DMF (125 μL, 1.614 mmol) wasadded followed by the slow dropwise addition of oxalyl chloride (2.5 mL,28.66 mmol). The reaction mixture was allowed to stir at roomtemperature for 30 minutes. The reaction mixture was concentrated underreduced pressure. Additional dichloromethane (˜5 mL) was added, and thesolution was again concentrated to dryness. The remaining residue wastaken up in NMP (2.7 mL) and added to a prepared solution of4-aminopyridine-2-carboxamide (833 mg, 6.074 mmol) and DIEA (4.2 mL,24.11 mmol) in NMP (2.7 mL). This reaction mixture was allowed to stirat 25° C. overnight. The reaction mixture was diluted with EtOAc (75 mL)and washed with water (2×75 mL), aqueous HCl (2×75 mL, 0.5 M) and brine(2×75 mL). The organic layer was dried over sodium sulfate, filtered andconcentrated under reduced pressure. The crude product waschromatographed on a silica gel column eluting with a EtOAc/hexanegradient to provide4-[[2-chloro-6-fluoro-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(430 mg, 32%) as a white solid. ESI-MS m/z calc. 361.0241, found 362.1(M+1)⁺; Retention time (Method B): 1.25 minutes. ¹H NMR (400 MHz,DMSO-d6) δ 11.54 (s, 1H), 8.59 (d, J=5.4 Hz, 1H), 8.34 (d, J=2.2 Hz,1H), 8.22-8.05 (m, 2H), 7.81 (dd, J=5.5, 2.2 Hz, 1H), 7.77-7.59 (m, 2H)ppm.

Step 2:4-[[2-chloro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(191)

A mixture of4-[[2-chloro-6-fluoro-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(30 mg, 0.0829 mmol), 2-methoxy-4-(trifluoromethoxy)phenol (56 mg, 0.269mmol), K₂CO₃ (36 mg, 0.261 mmol), and DMSO (150 μL) was stirred at 120°C. for 30 minutes. The reaction was diluted with DMSO (500 uL),filtered, and purified by reverse phase preparative chromatography usinga C18 column and a gradient eluent of 1 to 99% acetonitrile in water (5mM hydrochloric acid) to give4-[[2-chloro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(29 mg, 61%) as a white solid. ESI-MS m/z calc. 549.0526, found 550.0(M+1)⁺; Retention time (Method B): 1.78 minutes. ¹H NMR (400 MHz,DMSO-d6) δ 11.50 (s, 1H), 8.57 (d, J=5.5 Hz, 1H), 8.38 (d, J=2.1 Hz,1H), 8.29-8.07 (m, 1H), 8.03-7.81 (m, 2H), 7.81-7.60 (m, 1H), 7.35 (d,J=8.8 Hz, 1H), 7.27 (d, J=2.7 Hz, 1H), 7.05 (ddq, J=8.8, 2.5, 1.2 Hz,1H), 6.81 (d, J=8.9 Hz, 1H), 3.80 (s, 3H) ppm.

The compounds set forth in Table 24 were prepared by methods analogousto the preparation of compound 191.

TABLE 24 Additional Compounds Prepared By Methods Analogous to Example39. Cmpd No. Compound Name LC/MS NMR (shifts in ppm) 1924-[[2-chloro-6-[2- ESI-MS m/z 1H NMR (400 MHz, DMSO-d6) δ 11.52chloro-4- calc. 553.00305, (d, J = 3.1 Hz, 1H), 8.56 (d, J = 5.5 Hz,(trifluoromethoxy)phenoxy]- found 553.9 1H), 8.35 (d, J = 2.2 Hz, 1H),8.14 (s, 1H), 3- (M + 1)+; 7.94 (d, J = 9.0 Hz, 1H), 7.90-7.78 (m,(trifluoromethyl)benzoyl]ami- Retention time 2H), 7.70 (s, 1H), 7.52 (d,J = 1.6 Hz, 2H), no]pyridine-2- (Method B): 7.00 (d, J = 8.9 Hz, 1H).carboxamide 1.83 minutes 193 4-[[2-chloro-6-(3,4- ESI-MS m/z 1H NMR (400MHz, DMSO-d6) δ 11.54 difluoro-2-methoxy- calc. 501.05148, (s, 1H), 8.57(d, J = 5.5 Hz, 1H), 8.38 (d, phenoxy)-3- found 502.0 J = 2.1 Hz, 1H),8.27-8.00 (m, 1H), 8.00- (trifluoromethyl)benzoyl]ami- (M + 1)+; 7.79(m, 2H), 7.79-7.64 (m, 1H), 7.29 (td, no]pyridine-2- Retention time J =9.7, 8.4 Hz, 1H), 7.15 (ddd, J = 9.3, carboxamide Method B): 5.1, 2.2Hz, 1H), 6.94 (d, J = 8.8 Hz, 1H), 1.65 minutes. 3.85 (d, J = 1.2 Hz,3H).

Example 404-[[2-bromo-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(194)

Step 1: methyl4-[[2-bromo-6-fluoro-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxylate

To a solution of 2-bromo-6-fluoro-3-(trifluoromethyl)benzoic acid (25 g,87.106 mmol) in anhydrous pyridine (800 mL) (dried over CaH₂ for 18 h)was added methyl 4-aminopyridine-2-carboxylate (13.87 g, 91.159 mmol).The mixture was cooled to −14° C. and POCl₃ (8.4 mL, 90.119 mmol) wasadded dropwise. The reaction was stirred at −14° C. to −10° C. for 30minutes then warmed to RT and stirred for 3 h. The reaction was quenchedwith water (800 mL), extracted with EtOAc (2×1.2 L), and the combinedorganic layers were washed with water (3×500 mL), brine, dried overMgSO₄, filtered and concentrated under reduced pressure to providemethyl4-[[2-bromo-6-fluoro-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxylate(26.47 g, 72%) as an amber oil. ESI-MS m/z calc. 419.9733, found 421.0(M+1)⁺; Retention time (Method H): 4.31 minutes. This material was useddirectly in the next step without further purification.

Step 2:4-[[2-bromo-6-fluoro-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide

To a solution of methyl4-[[2-bromo-6-fluoro-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxylate(26.47 g, 62.85 mmol) in CH₃CN (312 mL) was added NH₄Cl (1.18 g, 22.06mmol) and NH₄OH (334 mL of 28% w/v, 2.669 mol) and the reaction wasstirred at RT for 5 h. Reaction mixture was diluted with EtOAc (1 L) andwashed with water (350 mL×2), brine, dried over MgSO₄, filtered, andconcentrated under reduced pressure. The residue was purified by silicagel chromatography using an EtOAc (containing 2% of 7N NH₃/MeOH)/hexanesgradient) to provide 8.69 g of product as a sticky off-white foam. Anadditional 5 g of product containing fractions contaminated with animpurity were re-purified by silica gel chromatography using an EtOAc(containing 2% of 7N NH₃/MeOH)—hexanes gradient and the purified sampleswere combined to give4-[[2-bromo-6-fluoro-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(12.699 g, 49%). ESI-MS m/z calc. 404.9736, found 406.8 (M+1)⁺;Retention time (Method H): 4.18 minutes.

Step 3:4-[[2-bromo-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(194)

4-[[2-bromo-6-fluoro-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(250 mg, 0.616 mmol) and 2-methoxy-4-(trifluoromethoxy)phenol (141 mg,0.677 mmol) were combined and dissolved in DMSO (0.5 mL). Solidpotassium carbonate (255 mg, 1.845 mmol) was added. The reaction mixturewas allowed to stir overnight at 75° C. The reaction mixture wasfiltered purified by silica gel chromatography using a EtOAc/hexanegradient to give4-[[2-bromo-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(325 mg, 82%) as a white solid. ¹H NMR (400 MHz, DMSO-d6) δ 11.39 (s,1H), 8.55 (d, J=5.5 Hz, 1H), 8.36 (d, J=2.1 Hz, 1H), 8.10 (d, J=2.9 Hz,1H), 7.88-7.82 (m, 2H), 7.66 (d, J=2.9 Hz, 1H), 7.32 (d, J=8.8 Hz, 1H),7.26 (d, J=2.7 Hz, 1H), 7.04 (ddq, J=8.8, 2.4, 1.2 Hz, 1H), 6.83 (d,J=8.8 Hz, 1H), 3.80 (s, 3H) ppm. ESI-MS m/z calc. 593.0021, found 596.1(M+3)+; Retention time (Method B): 1.52 minutes.

The compounds set forth in Table 25 were prepared by methods analogousto the preparation of compound 194.

TABLE 25 Additional Compounds Prepared By Methods Analogous to Example40. Cmpd No. Compound Name LC/MS NMR (shifts in ppm) 1954-[[2-bromo-6-[3-fluoro-2- ESI-MS m/z ¹H NMR (400 MHz, DMSO-d₆) δmethoxy-4- calc. 610.9927, 11.48 (s, 1H), 8.56 (d, J = 5.5 Hz,(trifluoromethoxy)phenoxy]-3- found 614.1 1H), 8.36 (d, J = 2.1 Hz, 1H),8.12 (s, (trifluoromethyl)benzoyl]ami- (M + 1)+; 1H), 7.89 (d, J = 9.0Hz, 1H), 7.82 no]pyridine-2-carboxamide Retention time (dd, J = 5.6, 2.2Hz, 1H), 7.68 (s, 1H), (Method B): 7.41 (t, J = 8.7 Hz, 1H), 7.19 (dd, J= 1.82 minutes 9.2, 2.1 Hz, 1H), 7.07 (d, J = 8.9 Hz, 1H), 3.85 (s, 3H).

Example 414-[[3-cyclopropyl-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzoyl]amino]pyridine-2-carboxamide(196)

Step 1: 3-bromo-6-iodo-2-methyl-benzoic acid

A solution of 3-bromo-2-methyl-benzoic acid (5000 mg, 23.25 mmol),Pd(OAc)₂ (262 mg, 1.166 mmol), I₂ (7.67 g, 30.22 mmol), and PhI(OAc)₂(9.74 g, 30.22 mmol) in DMF (130 mL) was heated at 100° C. for 16 hours.The mixture was cooled to RT and the DMF was removed under reducedpressure. To the residue was added DCM and sat. Na₂S₂O₃ and the mixtureas stirred for 15 minutes. To the mixture was added 1N HCl until the pHwas <3 and the layers were separated. The aqueous layer was extractedwith DCM (3×) and the combined organics were washed with a mixture ofsat. Na₂SO₃ and 1 N HCl. The organic phase was dried over Na₂SO₄ andconcentrated under reduced pressure. The residue was purified by mediumpressure reverse phase chromatography (C18, CH₃CN/water (5 mM HCl)) togive 3-bromo-6-iodo-2-methyl-benzoic acid (5.43 g, 69%) as a whitesolid. ¹H NMR (400 MHz, Chloroform-d) δ 7.60-7.47 (m, 1H), 7.33 (dd,J=8.5, 1.8 Hz, 1H), 2.49 (s, 3H) ppm.

Step 2: 1-bromo-3-fluoro-2-methoxy-4-(trifluoromethoxy)benzene

To a solution of 6-bromo-2-fluoro-3-(trifluoromethoxy)phenol (10 g,36.36 mmol) in DMF (20 mL) was added K₂CO₃ (6.5 g, 47.03 mmol) andiodomethane (4.1 mL, 65.86 mmol) and the mixture heated to 50° C. for 2h. The reaction mixture was allowed to cool down, filtered, concentratedunder reduced pressure and the residue was partitioned between diethylether (30 ml) and water (30 ml). The aqueous layer was further extractedwith diethyl ether (10 mL). Combined organic fractions were washed withbrine, dried over magnesium sulfate and concentrated under reducepressure to an oil. The product was purified by silica gelchromatography eluting with 100% petroleum ether to give1-bromo-3-fluoro-2-methoxy-4-(trifluoromethoxy)benzene (8.1 g, 77%) asan oil. ¹H NMR (400 MHz, Chloroform-d) δ 7.34 (dd, J=9.0, 2.4 Hz, 1H),6.95 (ddq, J=8.5, 7.2, 1.2 Hz, 1H), 4.01 (d, J=1.7 Hz, 3H) ppm.

Step 3: 3-fluoro-2-methoxy-4-(trifluoromethoxy)phenol

To a solution of 1-bromo-3-fluoro-2-methoxy-4-(trifluoromethoxy)benzene(7 g, 24.22 mmol) in dioxane (84 mL) was added(1E,4E)-1,5-diphenylpenta-1,4-dien-3-one palladium (554 mg, 0.6050mmol), di-tert-butyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (709mg, 1.670 mmol) and KOH (2.8 g, 49.91 mmol) followed by water (56 mL)and the mixture heated to 90° C. for 5 hours. The reaction mixture wasallowed to cool to RT, filtered and partitioned between diethyl ether(30 ml) and water (100 ml). The aqueous fraction was separated and wasacidified to ˜ pH 1 with 2M HCl and extracted twice with diethyl ether(2×50 ml). The combined organics where dried (MgSO₄) and concentratedunder reduced pressure to afford3-fluoro-2-methoxy-4-(trifluoromethoxy)phenol (3.6 g, 66%). ¹H NMR (400MHz, Chloroform-d) δ 6.91 (ddq, J=9.1, 7.8, 1.2 Hz, 1H), 6.70 (dd,J=9.1, 2.2 Hz, 1H), 5.92 (s, 1H), 4.04 (d, J=2.0 Hz, 3H) ppm.

Step 4:3-bromo-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzoicacid

To a pressure flask was added 3-bromo-6-iodo-2-methyl-benzoic acid (1000mg, 2.933 mmol), 3-fluoro-2-methoxy-4-(trifluoromethoxy)phenol (530 mg,2.344 mmol), cesium carbonate (1.2 g, 3.683 mmol), toluene (5.3 mL) anda stir bar. The reaction mixture was bubbled with nitrogen for 10minutes, then copper (I) iodide (446 mg, 2.342 mmol) was added. Theflask was flushed with nitrogen, capped, and heated at 100° C. withvigorous stirring for 16 hours. The mixture was allowed to cool, thendiluted with ethyl acetate and water. The water layer was acidified with1 M HCl and the product extracted into ethyl acetate. The biphasicmixture was filtered and the layers separated. The organic layer waswashed with brine, dried over MgSO₄, filtered and concentrated underreduced pressure. The residue was purified by silica gel chromatographyusing a gradient of MeOH in dichloromethane to give3-bromo-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzoicacid (453 mg, 44%) as a light yellow oil. ESI-MS m/z calc. 437.9726,found 439.0 (M+1)⁺; Retention time (Method B): 1.55 minutes. ¹H NMR (400MHz, DMSO-d6) δ 13.66 (s, 1H), 7.63 (d, J=8.9 Hz, 1H), 7.30 (ddq, J=9.5,8.4, 1.2 Hz, 1H), 6.87 (dd, J=9.3, 2.2 Hz, 1H), 6.78 (dd, J=8.8, 0.7 Hz,1H), 3.89 (s, 3H), 2.36 (s, 3H) ppm.

Step 5: tert-butyl3-bromo-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzoate

A mixture of3-bromo-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzoicacid (900 mg, 2.049 mmol), di-tert-butyl dicarbonate (670 mg, 3.070mmol), DMAP (50 mg, 0.4093 mmol), and tert-BuOH (900 μL), was heated at90° C. for 2 hours. The reaction mixture was directly purified by silicagel column chromatography using a gradient of EtOAc in hexanes to givetert-butyl3-bromo-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzoate(340 mg, 34%) as a clear oil. ¹H NMR (400 MHz, DMSO-d6) δ 7.67 (d, J=8.8Hz, 1H), 7.35-7.20 (m, 1H), 6.85 (dd, J=8.8, 0.7 Hz, 1H), 6.78 (dd,J=9.4, 2.2 Hz, 1H), 3.90 (d, J=0.8 Hz, 3H), 2.34 (s, 3H), 1.41 (s, 9H)ppm.

Step 6: tert-butyl3-cyclopropyl-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzoate

To a vial charged with tert-butyl3-bromo-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzoate(140 mg, 0.2827 mmol), palladium tritert-butylphosphane (approximately 7mg, 0.0141 mmol), and THF (1 mL) under an atmosphere of N₂ at 0° C. wasadded bromo(cyclopropyl)zinc (approximately 735 μL of 0.5 M, 0.367 mmol)in THF slowly and the reaction mixture was gradually warmed to roomtemperature over 1 h and stirred at RT for 15 minutes. The reactionmixture was quenched with 1N HCl, and the aq. layer was extracted withDCM (3×). The combined organic layers were dried over Na₂SO₄, filteredand concentrated. The residue was purified by column chromatographyusing a gradient of ethyl acetate in hexanes to yield tert-butyl3-cyclopropyl-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzoate(104 mg, 81%). ¹H NMR (400 MHz, Chloroform-d) δ 7.00 (d, J=8.5 Hz, 1H),6.89 (ddq, J=9.1, 7.9, 1.2 Hz, 1H), 6.62 (d, J=8.5 Hz, 1H), 6.59 (dd,J=9.3, 2.3 Hz, 1H), 3.98 (d, J=0.8 Hz, 3H), 2.43 (s, 3H), 1.84 (tt,J=8.5, 5.4 Hz, 1H), 1.47 (s, 9H), 1.02-0.87 (m, 2H), 0.67-0.53 (m, 2H)ppm.

Step 7:3-cyclopropyl-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzoicacid

To a solution of tert-butyl3-cyclopropyl-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzoate(105 mg, 0.230 mmol) in THF (0.75 mL) and water (165 μL, 9.203 mmol)cooled on ice was added TFA (2.65 mL, 34.50 mmol) over approximately 4minutes dropwise. The ice bath was removed and the solution was stirredat RT for 1 h. The stir bar was removed and the mixture was concentratedunder reduced pressure to give3-cyclopropyl-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzoicacid (89 mg, 92%). ESI-MS m/z calc. 400.09338, found 401.23 (M+1)⁺;Retention time (Method A): 0.81 minutes.

Step 8:4-[[3-cyclopropyl-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzoyl]amino]pyridine-2-carboxamide(196)

To a solution of3-cyclopropyl-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzoicacid (88 mg, 0.209 mmol) in DCM (2.5 mL) cooled in an ice bath was addedDMF (approximately 2 μL, 0.0295 mmol) followed by the dropwise additionof oxalyl chloride (approximately 36 μL, 0.418 mmol). The mixture wasstirred at on ice for 10 minutes then at RT for 2 h. The reaction wasconcentrated under reduced pressure and flushed with N₂ to afford theacid chloride, which was taken directly into the next step.

A solution of methyl 4-aminopyridine-2-carboxylate (approximately 79 mg,0.522 mmol) and DIEA (93 μL, 0.537 mmol) in DCM (2.5 mL) was cooled onice and the crude acid chloride in DCM (2.5 mL) was added dropwise. Theice bath was removed and the reaction mixture was stirred at RTovernight, and then at 50° C. for 2 hours. The reaction was cooled to RTand quenched into water and extract with DCM (3×). The combined organicswere dried over Na₂SO₄, filter and concentrated under reduced pressure.The major product was isolated by silica gel column chromatography usinga gradient of ethyl acetate in hexanes and was used directly in the nextstep. The isolated material was treated with NH₃ (10 mL of 7 M, 70.00mmol) in methanol for 8 hours. The solvent was removed under reducedpressure to give4-[[3-cyclopropyl-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzoyl]amino]pyridine-2-carboxamide(39 mg, 36%). ¹H NMR (400 MHz, Chloroform-d) δ 8.99 (s, 1H), 8.50 (d,J=5.6 Hz, 1H), 8.38 (s, 1H), 8.14-7.89 (m, 2H), 7.06 (d, J=8.6 Hz, 1H),6.99 (td, J=8.4, 7.8, 1.3 Hz, 1H), 6.85 (dd, J=9.2, 2.2 Hz, 1H), 6.58(d, J=8.5 Hz, 1H), 5.35 (s, 1H), 3.75 (d, J=1.5 Hz, 3H), 2.52 (s, 3H),1.87 (ddd, J=13.9, 8.5, 5.5 Hz, 1H), 1.03-0.91 (m, 2H), 0.60 (td, J=6.0,4.4 Hz, 2H) ppm. ESI-MS m/z calc. 519.1417, found 520.43 (M+1)⁺;Retention time Method B): 1.79 minutes.

The compounds set forth in Table 26 were prepared by methods analogousto the preparation of compound 196.

TABLE 26 Additional Compounds Prepared By Methods Analogous to Example41. Cmpd No. Compound Name LC/MS NMR (shifts in ppm) 1975-[[3-cyclopropyl-6-[3- ESI-MS m/z 1H NMR (400 MHz, DMSO-d6) δ 11.03fluoro-2-methoxy-4- calc. 519.1417, (s, 1H), 8.84 (s, 1H), 8.28 (d, J =11.0 (trifluoromethoxy)phenoxy]- found 520.0 Hz, 1H), 8.00 (d, J = 13.4Hz, 2H), 7.53 2-methyl- (M + 1)+; (s, 1H), 7.27 (s, 1H), 7.11 (d, J =8.6 Hz, benzoyl]amino]pyridine- Retention time 1H), 6.85 (d, J = 11.4Hz, 1H), 6.77 (d, J = 2-carboxamide (Method B): 8.5 Hz, 1H), 3.81 (s,3H), 2.41 (s, 3H), 1.9 minutes 1.93 (s, 1H), 0.96 (d, J = 14.5 Hz, 2H),0.62 (d, J = 11.1 Hz, 2H). 198 4-[[3-cyclopropyl-6-[2- ESI-MS m/z ¹H NMR(400 MHz, DMSO-d₆) δ 10.32 methoxy-4- calc. 515.1668, (s, 1H), 8.48 (d,J = 17.8 Hz, 2H), 8.17 (trifluoromethoxy)phenoxy]- found 516.0 (s, 1H),7.69 (s, 1H), 7.19-7.09 (m, 2-methyl- (M + 1)+; 2H), 7.09-7.04 (m, 1H),7.00-6.90 (m, benzoyl]amino]-5- Retention time 1H), 6.50 (d, J = 8.6 Hz,1H), 3.78 (s, methyl-pyridine-2- (Method B): 3H), 2.45 (s, 3H), 2.27 (s,3H), 1.92 (qd, carboxamide 1.85 minutes J = 8.2, 5.2 Hz, 1H), 1.07-0.82(m, 2H), 0.68-0.45 (m, 2H).

Example 424-[[6-[2-chloro-4-(trifluoromethoxy)phenoxy]-3-cyclopropyl-2-methyl-benzoyl]amino]pyridine-2-carboxamide(199)

Step 1:3-bromo-6-[2-chloro-4-(trifluoromethoxy)phenoxy]-2-methyl-benzoic acid

To a pressure flask was added 3-bromo-6-iodo-2-methyl-benzoic acid(1.170 g, 3.43 mmol), 2-chloro-4-(trifluoromethoxy)phenol (730 mg, 3.434mmol), cesium carbonate (1.8 g, 5.53 mmol), toluene (22 mL) and a stirbar. The reaction mixture was bubbled with nitrogen for 10 minutes, thencopper (I) iodide (660 mg, 3.465 mmol) was added. The flask was flushedwith nitrogen, capped, and heated at 100° C. with vigorous stirring for16 hours. The mixture was allowed to cool, then diluted with ethylacetate and water. The water layer was acidified with 1 M HCl and theproduct extracted into ethyl acetate. The aqueous layer was extractedwith additional ethyl acetate (3×50 mL). The combined organic layerswere washed with brine, dried over MgSO₄, filtered and concentratedunder reduced pressure. HPLC purification (30-99% CH₃CN/water (5 mMHCl)) provided3-bromo-6-[2-chloro-4-(trifluoromethoxy)phenoxy]-2-methyl-benzoic acid(800 mg, 55%) as a white solid. ESI-MS m/z calc. 423.9325, found 426.9(M+1)⁺; Retention time (Method A): 0.75 minutes. ¹H NMR (400 MHz,DMSO-d6) δ 13.65 (s, 1H), 7.76 (dd, J=2.9, 0.8 Hz, 1H), 7.66 (d, J=8.8Hz, 1H), 7.39 (ddd, J=9.0, 2.8, 1.1 Hz, 1H), 7.10 (d, J=9.0 Hz, 1H),6.77 (d, J=8.7 Hz, 1H), 2.36 (s, 3H) ppm.

Step 2: tert-butyl3-bromo-6-[2-chloro-4-(trifluoromethoxy)phenoxy]-2-methyl-benzoate

A mixture of3-bromo-6-[2-chloro-4-(trifluoromethoxy)phenoxy]-2-methyl-benzoic acid(795 mg, 1.868 mmol), tert-butoxycarbonyl tert-butyl carbonate (610 mg,2.795 mmol), DMAP (46 mg, 0.377 mmol), and t-BuOH (800 μL) was heated at90° C. for 1 hour (gas evolution during first several minutes). Thereaction mixture was cooled and additional tert-butoxycarbonyltert-butyl carbonate (610 mg, 2.795 mmol) added. The reaction wasstirred at 90° C. for 5 minutes with gas evolution. After gas evolutionhad ceased (5 min) the reaction mixture cooled to RT and directlypurified by silica gel column chromatography with an ethylacetate/hexanes gradient to provide tert-butyl3-bromo-6-[2-chloro-4-(trifluoromethoxy)phenoxy]-2-methyl-benzoate (845mg, 94%) as a clear, colorless oil. ESI-MS m z calc. 479.9951, found426.8 (M-tBu+1)+; Retention time (Method A): 0.84 minutes. ¹H NMR (400MHz, DMSO-d6) δ 7.76 (dd, J=3.0, 0.8 Hz, 1H), 7.73 (d, J=8.8 Hz, 1H),7.39-7.31 (m, 1H), 6.94 (dd, J=9.0, 1.4 Hz, 2H), 2.35 (s, 3H), 1.35 (s,9H) ppm.

Step 3: tert-butyl6-[2-chloro-4-(trifluoromethoxy)phenoxy]-3-cyclopropyl-2-methyl-benzoate

To a vial charged with tert-butyl3-bromo-6-[2-chloro-4-(trifluoromethoxy)phenoxy]-2-methyl-benzoate (140mg, 0.291 mmol), palladium tritert-butylphosphane (approximately 7 mg,0.0145 mmol), and THF (1 mL) under an atmosphere of N₂ at 0° C. wasadded bromo(cyclopropyl)zinc (639 μL of 0.5 M, 0.320 mmol) in THF slowlyand the reaction mixture was gradually warmed to room temperature over 1h and stirred at RT for 15 minutes. The reaction mixture was quenchedwith 1N HCl, the aqueous layer was extracted with DCM (3×). The combinedorganic layers were dried over Na₂SO₄, filtered and concentrated underreduced pressure. The residue was purified by silica gel chromatographyusing a gradient of ethyl acetate in hexanes to yield tert-butyl6-[2-chloro-4-(trifluoromethoxy)phenoxy]-3-cyclopropyl-2-methyl-benzoate(98 mg, 76%). 1H NMR (400 MHz, Chloroform-d) δ 7.33 (dq, J=2.9, 0.9 Hz,1H), 7.06-6.97 (m, 2H), 6.80 (d, J=9.0 Hz, 1H), 6.67 (d, J=8.5 Hz, 1H),2.44 (s, 3H), 1.85 (tt, J=8.5, 5.4 Hz, 1H), 1.44 (s, 9H), 1.00-0.87 (m,2H), 0.67-0.58 (m, 2H) ppm.

Step 4:6-[2-chloro-4-(trifluoromethoxy)phenoxy]-3-cyclopropyl-2-methyl-benzoicacid

To a solution of tert-butyl6-[2-chloro-4-(trifluoromethoxy)phenoxy]-3-cyclopropyl-2-methyl-benzoate(95 mg, 0.2145 mmol) in THF (750 μL) and water (150 μL) cooled on icewas added TFA (2.5 mL, 32.45 mmol) over approximately 4 minutesdropwise. The ice bath was removed and the solution was stirred at RTfor 1.25 h. The reaction was concentrated under reduced pressure to give6-[2-chloro-4-(trifluoromethoxy)phenoxy]-3-cyclopropyl-2-methyl-benzoicacid (83 mg, 100%). ESI-MS m/z calc. 386.05328, found 387.23 (M+1)⁺;Retention time (Method B): 0.83 minutes.

Step 5:4-[[6-[2-chloro-4-(trifluoromethoxy)phenoxy]-3-cyclopropyl-2-methyl-benzoyl]amino]pyridine-2-carboxamide(199)

To a solution of6-[2-chloro-4-(trifluoromethoxy)phenoxy]-3-cyclopropyl-2-methyl-benzoicacid (82 mg, 0.212 mmol) in DCM (2.5 mL) cooled in an ice bath was addedDMF (2 μL, 0.03 mmol) followed by the dropwise addition of oxalylchloride (37 μL, 0.425 mmol). The mixture was stirred at on ice for 10mins then at RT for 1.25 h. The reaction was concentrated under reducedpressure and flushed with N₂ to afford the acid chloride, which wastaken directly into the next step.

A solution of methyl 4-aminopyridine-2-carboxylate (80 mg, 0.53 mmol)and DIEA (94 μL, 0.545 mmol) in DCM (2.5 mL) was cool on ice and thecrude acid chloride in DCM (2.5 mL) was added drop wise. The ice bathwas removed and the reaction mixture was stirred at RT overnight, thenat 50° C. for 2 hours. The reaction was quenched into water and extractwith DCM (3×). The combined organics were dried over Na₂SO₄, filter andconcentrated under reduced pressure. The major product was isolated bysilica gel chromatography using a gradient of ethyl acetate in hexaneswhich was used directly in the next step. The isolated material wastreated with NH₃ (11.6 mL of 7 M, 81 mmol) in methanol for 28 hours. Thesolvent was removed under reduced pressure to give4-[[6-[2-chloro-4-(trifluoromethoxy)phenoxy]-3-cyclopropyl-2-methyl-benzoyl]amino]pyridine-2-carboxamide(53 mg, 49%). 1H NMR (400 MHz, Chloroform-d) δ 8.74 (s, 1H), 8.50 (d,J=5.6 Hz, 1H), 8.35 (s, 1H), 8.10 (s, 1H), 7.92 (s, 1H), 7.29 (d, J=2.3Hz, 1H), 7.16-6.91 (m, 3H), 6.57 (d, J=8.5 Hz, 1H), 5.25 (s, 1H), 2.51(s, 3H), 1.87 (td, J=8.4, 4.2 Hz, 1H), 1.04-0.93 (m, 2H), 0.70-0.53 (m,2H) ppm. ESI-MS m/z calc. 505.10162, found 506.38 (M+1)⁺; Retention time(Method B): 1.81 minutes.

Example 434-[[4-(difluoromethyl)-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-benzoyl]amino]pyridine-2-carboxamide(200)

Step 1: 2-bromo-5-(difluoromethyl)-1-fluoro-3-methyl-benzene

To 4-bromo-3-fluoro-5-methyl-benzaldehyde (5 g, 23.04 mmol) indichloromethane (30 mL) was added diethylaminosulfur trifluoride (36 mL,272.5 mmol) dropwise and the mixture was stirred under nitrogen for 5hours. The reaction was quenched whilst ice-cooled by drop wise additionof aqueous NaOH (2 M) until basic. The organic layer was separated,dried (MgSO4) and concentrated to give an orange oil. Purification bysilica gel chromatography with a ethyl acetate in heptane gradient gave2-bromo-5-(difluoromethyl)-1-fluoro-3-methyl-benzene (5.02 g, 91%). 1HNMR (500 MHz, DMSO-d6) δ 7.50-7.39 (m, 2H), 7.02 (t, J=55.5 Hz, 1H),2.46 (s, 3H) ppm.

Step 2: 4-(difluoromethyl)-2-fluoro-6-methyl-benzonitrile

2-bromo-5-(difluoromethyl)-1-fluoro-3-methyl-benzene (4.5 g, 18.83 mmol)in DMF (45 mL) was treated with Pd(PPh₃)₄ (1.12 g, 0.969 mmol) andZn(CN)₂ (2.641 g, 22.49 mmol) then degassed by a nitrogen purge andheated at 120° C. under nitrogen for 5 hours. The cooled mixture wasdiluted with EtOAc and washed with sat. aq. NaHCO₃ (2×), brine (2×) andwater. The organic layer was dried over MgSO₄ and concentrated underreduced pressure. The residue as purified by silica gel chromatographywith an ethyl acetate in heptane gradient to give4-(difluoromethyl)-2-fluoro-6-methyl-benzonitrile (2.908 g, 83%). 1H NMR(500 MHz, DMSO-d6) δ 7.59 (d, J=9.5 Hz, 1H), 7.57 (s, 1H), 7.10 (t,J=55.1 Hz, 1H), 2.57 (s, 3H) ppm.

Step 3:4-(difluoromethyl)-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-benzonitrile

2-Methoxy-4-(trifluoromethoxy)phenol (670.7 mg, 3.222 mmol),4-(difluoromethyl)-2-fluoro-6-methyl-benzonitrile (571 mg, 3.085 mmol)and Cs₂CO₃ (1.12 g, 3.437 mmol) were combined in DMF (3.5 mL), degassedby multiple N₂ flush and vacuum cycles and then heated at 80° C. for 2.5hours. Additional Cs₂CO₃ (203 mg, 0.624 mmol) and2-methoxy-4-(trifluoromethoxy)phenol (130 mg, 0.624 mmol) were added andheating was continued for 2 hours. The mixture was allowed to cool. Themixture was diluted with EtOAc and washed with 2M NaOH (2×) and brine(2×). The organic layer dried over MgSO₄ and concentrated under reducedpressure to give4-(difluoromethyl)-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-benzonitrile(1.316 g, 114%). This was used without further purification. 1H NMR (500MHz, DMSO-d6) δ 7.41 (d, J=8.8 Hz, 1H), 7.36 (s, 1H), 7.30 (d, J=2.7 Hz,1H), 7.07 (ddq, J=8.7, 2.4, 1.1 Hz, 1H), 6.99 (t, J=55.2 Hz, 1H), 6.68(s, 1H), 3.79 (s, 3H), 2.58 (s, 3H) ppm.

Step 4:4-(difluoromethyl)-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-benzamide

4-(Difluoromethyl)-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-benzonitrile(1.316 g, 3.526 mmol) in EtOH (13 mL) and NaOH (17 mL of 2 M, 34.00mmol) was stirred at 90° C. for 1.5 hours. Additional NaOH (2 g, 50.00mmol) was added and heating was continued for 6 hours. The mixture wasallowed to cool and then diluted with EtOAc and washed with brine. Theorganic layer was dried (MgSO4) and concentrated under reduced pressureto give4-(difluoromethyl)-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-benzamide(1.34 g, 97%). 1H NMR (500 MHz, DMSO-d6) δ 7.83 (t, J=2.2 Hz, 1H),7.65-7.55 (m, 1H), 7.21 (d, J=2.8 Hz, 1H), 7.18 (s, 1H), 7.14 (d, J=8.8Hz, 1H), 7.01-6.96 (m, 1H), 6.86 (d, J=55.7 Hz, 1H), 6.63 (s, 1H), 3.82(s, 3H), 2.36 (s, 3H) ppm.

Step 5: methyl4-[[4-(difluoromethyl)-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-benzoyl]amino]pyridine-2-carboxylate

A solution of methyl 4-bromopyridine-2-carboxylate (87.2 mg, 0.404mmol), Xantphos (36.4 mg, 0.0629 mmol), cesium carbonate (246 mg, 0.755mmol), Pd(OAc)₂ (11.2 mg, 0.0499 mmol) and4-(difluoromethyl)-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-benzamide(130 mg, 0.332 mmol) in dioxane (3 mL) was degassed with multiplenitrogen flush-vacuum cycles and then heated at 100° C. under nitrogenfor 2.75 hours. The mixture was diluted with EtOAc and washed with sat.aq. NaHCO₃. The organic layer was dried over MgSO₄ and concentratedunder reduced pressure to give methyl4-[[4-(difluoromethyl)-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-benzoyl]amino]pyridine-2-carboxylate(174.9 mg, 100%). ESI-MS m/z calc. 526.11633, found 527.6 (M+1)⁺;Retention time (Method D): 0.91 minutes.

Step 6:4-[[4-(difluoromethyl)-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-benzoyl]amino]pyridine-2-carboxamide(200)

Methyl4-[[4-(difluoromethyl)-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-benzoyl]amino]pyridine-2-carboxylate(175 mg, 0.3324 mmol) was dissolved in ammonia (in methanol) (3 mL of 7M, 21.00 mmol) and stirred at RT overnight. Purification by C18 reversephase HPLC gave4-[[4-(difluoromethyl)-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-benzoyl]amino]pyridine-2-carboxamide(68.2 mg, 40%). 1H NMR (500 MHz, DMSO-d6) δ 11.13 (s, 1H), 8.53 (d,J=5.4 Hz, 1H), 8.36 (d, J=2.2 Hz, 1H), 8.07 (d, J=2.9 Hz, 1H), 7.85 (dd,J=5.5, 2.2 Hz, 1H), 7.63 (d, J=2.9 Hz, 1H), 7.28 (s, 1H), 7.25 (d, J=8.8Hz, 1H), 7.20 (d, J=2.7 Hz, 1H), 7.01 (ddd, J=8.8, 2.7, 1.3 Hz, 1H),6.93 (d, J=55.6 Hz, 1H), 6.71 (s, 1H), 3.78 (s, 3H), 2.39 (s, 3H) ppm.ESI-MS m/z calc. 511.11667, found 512.5 (M+1)⁺; Retention time (MethodE): 3.08 minutes.

Example 44N-(2-carbamoyl-4-pyridyl)-5,6-dicyclopropyl-3-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-2-carboxamide(201)

Step 1: methyl 5,6-dicyclopropyl-3-fluoro-pyridine-2-carboxylate

A mixture of methyl 5-bromo-6-chloro-3-fluoro-pyridine-2-carboxylate (1g, 3.725 mmol), cyclopropyl boronic acid (2 g, 23.28 mmol), K₃PO₄ (2.8g, 13.19 mmol), Pd(OAc)₂ (170 mg, 0.757 mmol) and tricyclohexylphosphane(105 mg, 0.374 mmol) in toluene (20 mL) and water (5 mL) was heated at100° C. for 24 hours. Additional cyclopropylboronic acid (640 mg, 7.451mmol) was added and the reaction mixture heated for a further 24 h. Thereaction mixture was cooled to RT and diluted with water (20 mL) andEtOAc (20 mL) and the layers were separated. The aqueous layer wasextracted with EtOAc (2×25 mL) and the combined organic layers werewashed with saturated aqueous sodium carbonate solution, dried (MgSO₄)and concentrated under reduced pressure to give methyl5,6-dicyclopropyl-3-fluoro-pyridine-2-carboxylate (910 mg, 68%) as apale brown oil. This was used without purification. ESI-MS m/z calc.235.10086, found 236.6 (M+1)⁺; Retention time (Method D): 0.87 minutes.

Step 2:5,6-dicyclopropyl-3-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-2-carboxylicacid

To methyl 5,6-dicyclopropyl-3-fluoro-pyridine-2-carboxylate (300 mg,0.8289 mmol) in DMF (5 mL) was added2-methoxy-4-(trifluoromethoxy)phenol (173 mg, 0.831 mmol) and cesiumcarbonate (810 mg, 2.486 mmol) and the resulting mixture was heated at90° C. for 48 h. The reaction mixture was cooled to RT and diluted withwater (10 mL) and ethyl acetate (10 mL) and the layers were separated.The aqueous layer was extracted with EtOAc (2×5 mL). The aqueous layerwas acidified to pH3 by addition of 1N HCl and then extracted with EtOAc(3×10 mL). The combined organic extracts were dried over MgSO₄ andconcentrated under reduced pressure to give crude (approximately 60%pure) of5,6-dicyclopropyl-3-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-2-carboxylicacid (190 mg, 52%) as a dark oil which was taken on into the next stepwithout purification. ESI-MS m/z calc. 409.1137, found 410.6 (M+1)⁺;Retention time (Method D): 0.64 minutes.

Step 3:N-(2-carbamoyl-4-pyridyl)-5,6-dicyclopropyl-3-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-2-carboxamide(201)

DMF (5 μL, 0.0646 mmol) and oxalyl chloride (0.15 mL, 1.72 mmol) wasadded to an ice cooled solution of crude5,6-dicyclopropyl-3-fluoro-pyridine-2-carboxylic acid (187 mg,approximately 60% pure) in DCM (4 mL) and the resulting mixture stirredat RT for 2 h. The reaction mixture was concentrated under reducedpressure and the residue dissolved in DCM (4 mL) and methyl4-aminopyridine-2-carboxylate (250 mg, 1.643 mmol) and Et₃N (100 μL,0.718 mmol) was added and the resulting mixture stirred at RT overnight.The reaction mixture was concentrated under reduced pressure and thenammonia in MeOH (3 mL of 7 M, 21.00 mmol) was added and the resultingmixture stirred at RT overnight. The reaction mixture was concentratedunder reduced pressure and purified by C18 HPLC to yieldN-(2-carbamoyl-4-pyridyl)-5,6-dicyclopropyl-3-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-2-carboxamide(4.96 mg, 7%) as a white powder. 1H NMR (500 MHz, DMSO-d6) δ 10.69 (s,1H), 8.50 (d, J=5.3 Hz, 1H), 8.34 (d, J=2.1 Hz, 1H), 8.07 (d, J=2.8 Hz,1H), 7.90 (dd, J=5.5, 2.2 Hz, 1H), 7.61 (d, J=2.9 Hz, 1H), 7.14 (d,J=2.5 Hz, 1H), 6.95-6.84 (m, 3H), 3.79 (s, 3H), 2.55 (td, J=8.1, 4.1 Hz,1H), 2.24 (tt, J=8.5, 5.4 Hz, 1H), 1.15 (dq, J=4.9, 3.4 Hz, 2H), 1.02(ddt, J=8.5, 6.5, 4.1 Hz, 4H), 0.67-0.60 (m, 2H) ppm. ESI-MS m/z calc.528.16205, found 529.6 (M+1)⁺; 527.8 (M−1)⁻; Retention time (Method E):3.51 minutes.

Example 454-[[2,2-difluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-methyl-1,3-benzodioxole-5-carbonyl]amino]pyridine-2-carboxamide(202)

Step 1: 2,2-difluoro-6-iodo-4-methyl-1,3-benzodioxole-5-carboxylic acid

To 2,2-difluoro-4-methyl-1,3-benzodioxole-5-carboxylic acid (2 g, 9.253mmol), was added palladium(II) acetate (340 mg, 1.514 mmol),tetrabutylammonium iodide (3.6 g, 9.746 mmol),(acetyloxy)(phenyl)-lambda3-iodanyl acetate (6.28 g, 19.50 mmol), iodine(4.94 g, 19.46 mmol) and DCE (20 mL) and the reaction was stirred at 60°C. for 14 h. Additional palladium(II) acetate (340 mg, 1.514 mmol),tetrabutylammonium iodide (3.6 g, 9.746 mmol),(acetyloxy)(phenyl)-lambda3-iodanyl acetate (6.28 g, 19.50 mmol) andiodine (4.94 g, 19.46 mmol) were added and to the reaction and stirredat 60° C. for 93 h. The reaction was acidified with 1 M HCl and asaturated aqueous solution of sodium bisulfite was added. The reactionwas extracted with DCM (×3). The combined organic layers were washedwith brine and dried over Na₂SO₄, filtered and the solvent wasevaporated under reduced pressure. The crude product was dissolved inDMSO, filtered and purified using a reverse phase HPLC C18 column(CH₃CN/water (5 mM HCi) gradient) to yield2,2-difluoro-6-iodo-4-methyl-1,3-benzodioxole-5-carboxylic acid (1.59 g,50%) as a brown solid. ¹H NMR (400 MHz, DMSO-d6) δ 13.80 (s, 1H), 7.82(s, 1H), 2.26 (s, 3H) ppm. ESI-MS m/z calc. 341.92004, found 343.0(M+1)⁺; Retention time (Method C): 2.02 minutes.

Step 2:2,2-difluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-methyl-1,3-benzodioxole-5-carboxylicacid

A flask containing2,2-difluoro-6-iodo-4-methyl-1,3-benzodioxole-5-carboxylic acid (1.47 g,4.298 mmol), toluene (30 mL) and a stirrer bar was flushed with N₂ for10 min. 2-Methoxy-4-(trifluoromethoxy)phenol (901.4 mg, 4.331 mmol) andcesium carbonate (2.89 g, 8.87 mmol) were added to the reaction andflushed with N₂ for 10 min. Copper (I) iodide (177 mg, 0.933 mmol) wasadded to the reaction and flushed with N₂ for 10 min. The reaction wasstirred at 60° C. with vigorous stirring under N₂ for 14 h. Additional2-methoxy-4-(trifluoromethoxy)phenol (901 mg, 4.331 mmol), cesiumcarbonate (2.89 g, 8.870 mmol), iodocopper (177 mg, 0.933 mmol) andtoluene (24 mL) were added to the reaction, which was flushed with N₂for 10 min and the reaction was stirred at 60° C. for 1 h. The mixturewas allowed to cool, and then diluted with ethyl acetate and water andacidified with 1 M HCl. The two layers were separated. The aqueous layerwas extracted with EtOAc (3×). The combined organic layers were filteredand the filtrate was washed with water and brine, dried over sodiumsulfate, filtered through a plug of celite and concentrated underreduced pressure. The crude product was dissolved in DMSO, filtered andpurified using a reverse phase HPLC C18 column (CH₃CN/water (5 mM HCl)gradient) to yield2,2-difluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-methyl-1,3-benzodioxole-5-carboxylicacid (370.0 mg, 20%) as a brown solid. ESI-MS m/z calc. 422.04248, found423.4 (M+1)⁺; Retention time (Method C): 2.75 minutes.

Step 3:2,2-difluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-methyl-1,3-benzodioxole-5-carbonylchloride

To2,2-difluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-methyl-1,3-benzodioxole-5-carboxylicacid (370 mg, 0.8762 mmol) and DMF (15 μL, 0.194 mmol) in DCM (3.5 mL)at 0° C. was added oxalyl chloride (216 μL, 2.476 mmol) dropwise under aN₂ atmosphere. The ice bath was removed after 10 min and the reactionwas stirred at room temperature for 1.5 h. The mixture was concentratedunder reduced pressure to afford2,2-difluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-methyl-1,3-benzodioxole-5-carbonylchloride, which was used directly in the next step.

Step 4:4-[[2,2-difluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-methyl-1,3-benzodioxole-5-carbonyl]amino]pyridine-2-carboxamide(202)

To 4-aminopyridine-2-carboxamide (approximately 39 mg, 0.281 mmol) inNMP (500 μL), and DIEA (approximately 122 μL, 0.704 mmol) at 0° C. wasadded a solution of2,2-difluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-methyl-1,3-benzodioxole-5-carbonylchloride (62 mg, 0.1407 mmol) in NMP (500 μL) slowly. The reaction wasstirred at RT for 19 hours follow by 75° C. for 7 hours. The crudeproduct was filtered and purified using a reverse phase HPLC C18 column(CH₃CN/water (5 mM HCl) gradient) to yield4-[[2,2-difluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-methyl-1,3-benzodioxole-5-carbonyl]amino]pyridine-2-carboxamide(23.0 mg, 30%). 1H NMR (400 MHz, DMSO-d6) δ 11.10 (s, 1H), 8.51 (d,J=5.5 Hz, 1H), 8.31 (d, J=2.1 Hz, 1H), 8.09 (d, J=2.8 Hz, 1H), 7.80 (dd,J=5.5, 2.2 Hz, 1H), 7.64 (d, J=2.8 Hz, 1H), 7.16-7.10 (m, 2H), 7.01-6.86(m, 2H), 3.74 (s, 3H), 2.29 (s, 3H) ppm. ESI-MS m/z calc. 541.0908,found 542.1 (M+1)⁺; Retention time (Method C): 2.67 minutes.

The compounds set forth in Table 27 were prepared by methods analogousto the preparation of compound 202.

TABLE 27 Additional Compounds Prepared By Methods Analogous to Example45. Cmpd No. Compound Name LC/MS NMR (shifts in ppm) 2035-[[2,2-difluoro-6-[2- ESI-MS m/z 1H NMR (400 MHz, DMSO-d6) δ methoxy-4-calc. 541.0908, 10.99 (s, 1H), 8.82 (dd, J = 2.5, 0.7(trifluoromethoxy)phenoxy]- found 542.2 Hz, 1H), 8.23 (dd, J = 8.6, 2.5Hz, 4-methyl-1,3- (M + 1)+; 1H), 8.09-7.93 (m, 2H), 7.54 (s,benzodioxole-5- Retention time 1H), 7.18-7.06 (m, 2H), 7.02-6.86carbonyl]amino]pyridine- (Method C): (m, 2H), 3.73 (s, 3H), 2.30 (s,3H). 2-carboxamide 2.67 minutes

Example 464-[[3-(3,3-difluorocyclobutoxy)-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzoyl]amino]pyridine-2-carboxamide(204)

Step 1: 3-(3,3-difluorocyclobutoxy)-2-methyl-benzoic acid

A solution of 3,3-difluorocyclobutanol (2 g, 18.50 mmol) and pyridine(4.9 mL, 60.58 mmol) in DCM (20 mL) was cooled to −78° C. and triflicanhydride (4.1 mL, 24.37 mmol) was added dropwise. After the addition,the cooling bath was replaced with and ice bath and the reaction mixturestirred for an additional 20 minutes. The reaction mixture was poured into 0.1N HCl and extracted with DCM (3×). The combined organics werewashed with 0.1N HCl (2×), water, brine, dried over Na₂SO₄, filteredthrough a short plug of silica and evaporated to dryness to give(3,3-difluorocyclobutyl) trifluoromethanesulfonate that was useddirectly in the next step.

A solution of methyl 3-hydroxy-2-methyl-benzoate (2 g, 12.04 mmol) inDMF (20 mL) was cooled to 0° C., NaH (950 mg of 60% w/w, 23.75 mmol) wasadded in portions and the reaction mixture stirred at this temperaturefor 10 minutes. A solution of (3,3-difluorocyclobutyl)trifluoromethanesulfonate in DMF (5 mL) was added dropwise over 5minutes, the cooling bath was removed and the reaction mixture wasstirred at RT for 16 hours. The reaction mixture was poured in to water,the pH was adjusted with 1N HCl to ˜2 and the mixture was extracted withEtOAc (3×). The organics phases were combined washed with 0.1N HCl (2×),brine and concentrated under reduced pressure. The residue was purifiedby silica gel column chromatography using a EtOAc in hexane gradient togive 3-(3,3-difluorocyclobutoxy)-2-methyl-benzoic acid (1.11 g, 38%) asan off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 12.88 (s, 1H), 7.34 (d,J=8.1 Hz, 1H), 7.22 (dd, J=8.0 Hz, 1H), 7.01 (dd, J=8.2, 1.2 Hz, 1H),4.86-4.71 (m, 1H), 3.29-3.14 (m, 2H), 2.80-2.61 (m, 2H), 2.34 (s, 3H)ppm.

Step 2: 3-(3,3-difluorocyclobutoxy)-6-iodo-2-methyl-benzoic acid

To a solution of 3-(3,3-difluorocyclobutoxy)-2-methyl-benzoic acid (220mg, 0.908 mmol), iodine (461 mg, 1.817 mmol), and(acetyloxy)(phenyl)-lambda3-iodanyl acetate (585 mg, 1.816 mmol) in DMF(2.5 mL) was degased by bubbling nitrogen through the solution for 5min. To the reaction mixture was added palladium (II) acetate (33 mg,0.1470 mmol) and the reaction mixture was stirred at 100° C. for 45 min.The reaction mixture was poured into 0.1 N HCl and extracted with EtOAc(3×). The organics phases were combined, washed with brine, dried overNa₂SO₄ and concentrated under reduced pressure. The residue was purifiedby silica gel column chromatography with a MeOH in DCM gradient to give3-(3,3-difluorocyclobutoxy)-6-iodo-2-methyl-benzoic acid (160 mg, 48%)as a cream solid. ESI-MS m/z calc. 367.9721, found 369.0 (M+1)⁺;Retention time (Method A): 0.55 minutes.

Step 3:3-(3,3-difluorocyclobutoxy)-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzoicacid

A suspension of 3-(3,3-difluorocyclobutoxy)-6-iodo-2-methyl-benzoic acid(160 mg, 0.435 mmol), 2-methoxy-4-(trifluoromethoxy)phenol (145 mg,0.697 mmol) and Cs₂CO₃ (296 mg, 0.909 mmol) was degassed by bubblingnitrogen through the solution for 3 min, copper (I) iodide (19 mg,0.0998 mmol) was added and the reaction mixture stirred at 100° C. for 1hour. The reaction mixture was poured into water, the pH was adjusted to2 with 1N HCl and the mixture was extracted with EtOAc (3×). The organicphases were combined, washed with 0.1N HCl, brine, dried over sodiumsulfate and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography with a EtOAc in hexanesgradient to give3-(3,3-difluorocyclobutoxy)-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzoicacid (58 mg, 30%) as an off-white solid. ESI-MS m/z calc. 448.09454,found 449.1 (M+1)⁺; Retention time (Method A): 0.68 minutes.

Step 4:4-[[3-(3,3-difluorocyclobutoxy)-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzoyl]amino]pyridine-2-carboxamide(204)

To a solution of3-(3,3-difluorocyclobutoxy)-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzoicacid (58 mg, 0.129 mmol) in DCM (1 mL) and DMF (12 μL, 0.155 mmol) wasadded oxalyl chloride (25 μL, 0.287 mmol) and the reaction mixture wasstirred at RT for 15 min. The reaction mixture was then concentratedunder reduced pressure, toluene was added and the mixture wasconcentrated again under reduced pressure. The residue was taken up inDCM and added dropwise to a solution of 4-aminopyridine-2-carboxamide(29 mg, 0.212 mmol) and DIEA (68 μL, 0.390 mmol) in NMP (580.0 μL) andthe reaction mixture was stirred at RT for 16 hours. The reactionmixture was evaporated to half its original volume, diluted with MeOH,filtered and purification by HPLC (CH₃CN/Water (5 mM HCl) gradient) togive4-[[3-(3,3-difluorocyclobutoxy)-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzoyl]amino]pyridine-2-carboxamide(Hydrochloride salt) (8.2 mg, 10%) as a white solid. ESI-MS m/z calc.567.1429, found 568.1 (M+1)⁺; Retention time (Method B): 1.76 minutes.1H NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 8.50 (d, J=5.5 Hz, 1H), 8.33(d, J=2.1 Hz, 1H), 8.08 (s, 1H), 7.81 (dd, J=5.5, 2.2 Hz, 1H), 7.63 (s,1H), 7.10 (d, J=2.7 Hz, 1H), 7.05 (d, J=8.8 Hz, 1H), 6.95-6.88 (m, 2H),6.62 (d, J=8.9 Hz, 1H), 4.76 (m, J=11.7, 7.3 Hz, 1H), 3.73 (s, 3H),3.28-3.18 (m, 2H), 2.78-2.60 (m, 2H), 2.17 (s, 3H) ppm.

Example 47N-(6-carbamoyl-3-pyridyl)-5,6-dicyclopropyl-3-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-2-carboxamide(205)

Step 1:N-(6-carbamoyl-3-pyridyl)-5,6-dicyclopropyl-3-fluoro-pyridine-2-carboxamide

DMF (5 μL, 0.0646 mmol) was added to an ice cooled solution of5,6-dicyclopropyl-3-fluoro-pyridine-2-carboxylic acid (70 mg, 0.316mmol) (side product from example 44, step 1) and oxalyl chloride (100μL, 1.146 mmol) in DCM (2 mL) and the resulting mixture stirred at RTfor 2 h. The solvent was removed under reduced pressure and the residuedissolved in DCM (2 mL) and methyl 5-aminopyridine-2-carboxylate (50 mg,0.329 mmol) and Et₃N (100 μL, 0.718 mmol) were added and the resultingmixture stirred at RT overnight. The reaction mixture was concentratedunder reduced pressure and ammonia in methanol (2.5 mL of 7 M, 17.50mmol) was added and the resulting mixture stirred at RT over theweekend. The reaction mixture was concentrated under reduced pressure toleave a dark brown oil which was dissolved in DCM (10 mL) and water (10mL) and the layers separated. The organic layer was washed withadditional water (1×10 mL), dried over MgSO₄ and concentrated underreduced pressure. The residue was purified by chromatography on silicagel eluting with a EtOAc in petroleum ether gradient to giveN-(6-carbamoyl-3-pyridyl)-5,6-dicyclopropyl-3-fluoro-pyridine-2-carboxamide(56 mg, 42%) as a white powder. 1H NMR (500 MHz, DMSO-d6) δ 10.53 (s,1H), 8.99 (d, J=2.4 Hz, 1H), 8.33 (dd, J=8.5, 2.5 Hz, 1H), 8.09-8.02 (m,2H), 7.54 (s, 1H), 7.43 (d, J=11.7 Hz, 1H), 2.60-2.52 (m, 1H), 2.31(ddd, J=13.5, 8.4, 5.1 Hz, 1H), 1.23-1.15 (m, 2H), 1.14-1.06 (m, 2H),1.02 (dq, J=8.2, 3.5 Hz, 2H), 0.88-0.81 (m, 2H) ppm. ESI-MS m/z calc.340.13354, found 314.6 (M+1)⁺; 339.8 (M−1)⁻; Retention time (Method D):0.79 minutes.

Step 3:N-(6-carbamoyl-3-pyridyl)-5,6-dicyclopropyl-3-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-2-carboxamide(205)

A mixture of 2-methoxy-4-(trifluoromethoxy)phenol (15 mg, 0.0721 mmol),N-(6-carbamoyl-3-pyridyl)-5,6-dicyclopropyl-3-fluoro-pyridine-2-carboxamide(22 mg, 0.0646 mmol) and Cs₂CO₃ (63 mg, 0.193 mmol) in DMF (2 mL) washeated at 100° C. overnight. The reaction mixture was cooled to RT andpurified by HPLC to giveN-(6-carbamoyl-3-pyridyl)-5,6-dicyclopropyl-3-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-2-carboxamide(trifluoroacetic acid (2)) (4.8 mg, 10%) as a white powder. 1H NMR (500MHz, DMSO-d6) δ 10.61 (s, 1H), 8.90 (d, J=2.5 Hz, 1H), 8.26 (dd, J=8.5,2.4 Hz, 1H), 8.02 (d, J=8.6 Hz, 2H), 7.52 (s, 1H), 7.14 (d, J=2.5 Hz,1H), 6.95-6.86 (m, 3H), 3.78 (s, 3H), 2.56 (td, J=8.1, 4.0 Hz, 1H), 2.24(tt, J=8.4, 5.3 Hz, 1H), 1.15 (dd, J=5.0, 2.5 Hz, 2H), 1.08-0.96 (m,4H), 0.67-0.58 (m, 2H) ppm. ESI-MS m/z calc. 528.16205, found 529.6(M+1)⁺; 527.7 (M−1)⁻; Retention time (Method E): 3.49 minutes.

Example 485-[[6-[2-cyclopropyl-4-(trifluoromethoxy)phenoxy]-2-fluoro-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(206)

Step 1:5-[[6-bromo-2-fluoro-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide

6-Bromo-2-fluoro-3-(trifluoromethyl)benzoic acid (2.0 g, 6.968 mmol) wasdissolved in dichloromethane (28 mL). DMF (215 μL, 2.777 mmol) was addedfollowed by the slow dropwise addition of oxalyl chloride (2.7 mL, 30.95mmol). The reaction mixture was allowed to stir at RT for 30 minutes.The reaction mixture was concentrated under reduced pressure. Additionaldichloromethane (˜5 mL) was added, and the solution was againconcentrated to dryness. The remaining residue was taken up in NMP (6mL) and added to a prepared solution of 5-aminopyridine-2-carboxamide(1.4 g, 10.21 mmol) and DIEA (7.3 mL, 41.91 mmol) in NMP (6 mL). Thisreaction mixture was allowed to stir at 25° C. for 4 hours. The reactionmixture was purified by silica gel column chromatography using agradient of EtOAc in hexanes to give5-[[6-bromo-2-fluoro-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(1.5 g, 53%) as a white solid. ESI-MS m/z calc. 404.9736, found 406.1(M+1)⁺; Retention time (Method B): 1.01 minutes. 1H NMR (400 MHz,DMSO-d6) δ 11.45 (s, 1H), 8.86 (d, J=2.4 Hz, 1H), 8.31 (dd, J=8.5, 2.5Hz, 1H), 8.20-7.99 (m, 2H), 8.00-7.79 (m, 2H), 7.71-7.41 (m, 1H) ppm.

Step 2:5-[[6-[2-cyclopropyl-4-(trifluoromethoxy)phenoxy]-2-fluoro-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(206)

5-[[6-Bromo-2-fluoro-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(50 mg, 0.123 mmol), 2-cyclopropyl-4-(trifluoromethoxy)phenol(approximately 32 mg, 0.148 mmol), Cs₂CO₃ (approximately 60 mg, 0.185mmol), and copper (I) iodide (approximately 9 mg, 0.0492 mmol) intoluene (0.5 mL) were purged with nitrogen. The mixture was stirred at100° C. for 60 minutes. The reaction mixture was allowed to cool to RT,filtered, and purified by reverse phase chromatography using a C18column and a gradient of acetonitrile in water (5 mM hydrochloric acid)to give5-[[6-[2-cyclopropyl-4-(trifluoromethoxy)phenoxy]-2-fluoro-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(4.7 mg, 7%). ESI-MS m/z calc. 543.1029, found 544.0 (M+1)⁺; Retentiontime (Method B): 1.92 minutes. 1H NMR (400 MHz, DMSO-d6) δ 11.43 (s,1H), 8.85 (s, 1H), 8.30 (d, J=10.8 Hz, 1H), 8.10-7.96 (m, 2H), 7.87 (s,1H), 7.57 (s, 1H), 7.29 (s, 2H), 7.01 (s, 1H), 6.74 (d, J=8.9 Hz, 1H),1.98 (s, 1H), 0.87 (d, J=10.1 Hz, 2H), 0.71 (d, J=5.3 Hz, 2H) ppm.

The compounds set forth in Table 28 were prepared by methods analogousto the preparation of compound 206.

TABLE 28 Additional Compounds Prepared By Methods Analogous to Example48. Cmpd No. Compound Name LC/MS NMR (shifts in ppm) 2075-[[6-(3,4-difluoro-2- ESI-MS m/z 1H NMR (400 MHz, DMSO-d6) δ 11.44 (s,methyl-phenoxy)-2- calc. 469.08612, 1H), 8.85 (s, 1H), 8.30 (d, J = 6.1Hz, 1H), fluoro-3- found 470.0 8.15-7.98 (m, 2H), 7.84 (s, 1H), 7.58 (s,1H), (trifluoromethyl)benzoyl]ami- (M + 1)+; 7.41 (q, J = 9.4 Hz, 1H),7.08 (d, J = 13.2 Hz, no]pyridine-2- Retention time 1H), 6.77 (d, J =8.9 Hz, 1H), 2.11 (s, 3H). carboxamide (Method B): 1.68 minutes 2085-[[6-(4-chloro-2,6- ESI-MS m/z ¹H NMR (400 MHz, DMSO-d₆) δ 11.49 (s,dimethyl-phenoxy)-2- calc. 481.08163, 1H), 8.88 (d, J = 2.4 Hz, 1H),8.35 (dd, J = fluoro-3- found 482.0 8.7, 2.5 Hz, 1H), 8.20-8.00 (m, 2H),7.79 (t, (trifluoromethyl)benzoyl]ami- (M + 1)+; J = 8.7 Hz, 1H),7.71-7.52 (m, 1H), 7.33 (s, no]pyridine-2- Retention time 2H), 6.48 (d,J = 8.9 Hz, 1H), 2.10 (s, 6H). carboxamide (Method B) 1.86 minutes 2095-[[2-fluoro-6-[3- ESI-MS m/z ¹H NMR (400 MHz, DMSO-d₆) δ 11.45 (s,fluoro-2-methoxy-4- calc. 551.07275, 1H), 8.85 (d, J = 2.4 Hz, 1H), 8.30(dd, J = (trifluoromethoxy)phenoxy]- found 552.0 8.6, 2.5 Hz, 1H),8.17-7.98 (m, 2H), 7.87 (t, 3- (M + 1)+; J = 8.6 Hz, 1H), 7.60 (s, 1H),7.41 (t, J = 8.6 (trifluoromethyl)benzoyl]ami- Retention time Hz, 1H),7.23 (dd, J = 9.3, 2.1 Hz, 1H), 6.93 no]pyridine-2- (Method B): (d, J =8.9 Hz, 1H), 3.86 (s, 3H). carboxamide 1.86 minutes 2105-[[2-fluoro-6-[2- ESI-MS m/z ¹H NMR (400 MHz, DMSO-d₆) δ 11.42 (s,methoxy-4-(1,1,2,2,2- calc. 567.08405, 1H), 8.86 (d, J = 2.5 Hz, 1H),8.28 (dd, J = pentafluoroethyl)phenoxy]- found 568.0 8.6, 2.5 Hz, 1H),8.06 (d, J = 8.7 Hz, 2H), 3- (M + 1)+; 7.85 (t, J = 8.6 Hz, 1H),7.69-7.55 (m, 1H), (trifluoromethyl)benzoyl]ami- Retention time 7.47 (d,J = 8.4 Hz, 1H), 7.42 (d, J = 2.2 Hz, no]pyridine-2- (Method B): 1H),7.37 (dd, J = 8.7, 2.1 Hz, 1H), 6.79 (d, J carboxamide 1.89 minutes =8.9 Hz, 1H), 3.83 (s, 3H). 211 5-[[6-(2, 6-dimethoxy- ESI-MS m/z ¹H NMR(400 MHz, DMSO-d₆) δ 11.28 (s, 4-methyl-phenoxy)-2- calc. 493.1261, 1H),8.90 (d, J = 2.5 Hz, 1H), 8.34 (dd, J = fluoro-3- found 494.0 8.6, 2.5Hz, 1H), 8.07 (d, J = 8.6 Hz, 2H), (trifluoromethyl)benzoyl]ami- (M +1)+; 7.75 (t, J = 8.7 Hz, 1H), 7.68-7.52 (m, 1H), no]pyridine-2-Retention time 6.65 (s, 2H), 6.54 (d, J = 8.9 Hz, 1H), 3.72 (s,carboxamide (Method B): 6H), 2.33 (s, 3H). 1.71 minutes 2125-[[2-fluoro-3- ESI-MS m/z ¹H NMR (400 MHz, DMSO-d₆) δ 11.51 (s,(trifluoromethyl)-6- calc. 473.06104, 1H), 8.87 (d, J = 2.5 Hz, 1H),8.31 (dd, J = (2,4,6- found 474.0 8.5, 2.5 Hz, 1H), 8.08 (d, J = 8.6 Hz,2H), trifluorophenoxy)benzoyl]ami- (M + 1)+; 7.88 (t, J = 8.6 Hz, 1H),7.60 (s, 1H), 7.57- no]pyridine-2- Retention time 7.47 (m, 2H), 7.01 (d,J = 8.9 Hz, 1H). carboxamide (Method B): 1.54 minutes 2135-[[6-(2,4-dichloro-6- ESI-MS m/z ¹H NMR (400 MHz, DMSO-d₆) δ 11.46 (s,methyl-phenoxy)-2- calc. 501.027, 1H), 8.87 (d, J = 2.5 Hz, 1H), 8.35(dd, J = fluoro-3- found 502.0 8.6, 2.5 Hz, 1H), 8.21-7.97 (m, 2H), 7.81(t, (trifluoromethyl)benzoyl]ami- (M + 1)+; J = 8.6 Hz, 1H), 7.70 (d, J= 2.5 Hz, 1H), 7.60 no]pyridine-2- Retention time (s, 1H), 7.54 (d, J =2.5 Hz, 1H), 6.60 (d, J = carboxamide (Method B): 8.9 Hz, 1H), 2.19 (s,3H). 1.89 minutes 214 5-[[2-fluoro-6-(4- ESI-MS m/z ¹H NMR (400 MHz,DMSO-d₆) δ 11.45 (s, fluoro-2,3-dimethyl- calc. 465.11118, 1H), 8.87 (d,J = 2.5 Hz, 1H), 8.32 (dd, J = phenoxy)-3- found 466.0 8.7, 2.5 Hz, 1H),8.20-7.96 (m, 2H), 7.82 (t, (trifluoromethyl)benzoyl]ami- (M + 1)+; J =8.6 Hz, 1H), 7.60 (s, 1H), 7.24-6.97 (m, no]pyridine-2- Retention time2H), 6.60 (d, J = 8.9 Hz, 1H), 2.17 (d, J = 2.1 carboxamide (Method B):Hz, 3H), 2.08 (s, 3H). 1.81 minutes 215 5-[[2-fluoro-3- ESI-MS m/z ¹HNMR (400 MHz, DMSO-d₆) δ 11.47 (s, (trifluoromethyl)-6- calc. 473.06104,1H), 8.85 (d, J = 2.4 Hz, 1H), 8.30 (dd, J = (2,3,4- found 474.0 8.6,2.5 Hz, 1H), 8.19-8.01 (m, 2H), 7.89 (t, trifluorophenoxy)benzoyl]ami-(M + 1)+; J = 8.6 Hz, 1H), 7.60 (s, 1H), 7.55-7.40 (m, no]pyridine-2-Retention time 1H), 7.40-7.23 (m, 1H), 7.05 (d, J = 8.9 Hz, carboxamide(Method B): 1H). 1.66 minutes 216 5-[[2-fluoro-6-[3- ESI-MS m/z ¹H NMR(400 MHz, DMSO-d₆) δ 11.40 (s, fluoro-4- calc. 521.0622, 1H), 8.82 (d, J= 2.4 Hz, 1H), 8.26 (dd, J = (trifluoromethoxy)phenoxy]- found 522.08.6, 2.5 Hz, 1H), 8.05 (d, J = 8.6 Hz, 2H), 3- (M + 1)+; 7.94 (t, J =8.6 Hz, 1H), 7.67 (t, J = 9.2 Hz, (trifluoromethyl)benzoyl]ami-Retention time 1H), 7.63-7.55 (m, 1H), 7.51 (dd, J = 11.1,no]pyridine-2- (Method B): 2.9 Hz, 1H), 7.17 (d, J = 9.0 Hz, 1H), 7.10(d, carboxamide 1.82 minutes J = 8.8 Hz, 1H). 217 5-[[6-[3-chloro-4-ESI-MS m/z ¹H NMR (400 MHz, DMSO-d₆) δ 11.43 (s,(trifluoromethoxy)phenoxy]- calc. 537.03265, 1H), 8.82 (d, J = 2.4 Hz,1H), 8.26 (dd, J = 2-fluoro-3- found 538.0 8.6, 2.5 Hz, 1H), 8.05 (d, J= 8.7 Hz, 2H), (trifluoromethyl)benzoyl]ami- (M + 1)+; 7.93 (t, J = 8.6Hz, 1H), 7.66 (d, J = 10.6 Hz, no]pyridine-2- Retention time 2H), 7.59(s, 1H), 7.34 (dd, J = 9.0, 2.9 Hz, carboxamide (Method B): 1H), 7.09(d, J = 8.8 Hz, 1H). 1.89 minutes 218 5-[[6-(4-chloro-2- ESI-MS m/z ¹HNMR (400 MHz, DMSO-d₆) δ 11.42 (s, methyl-phenoxy)-2- calc. 467.06598,1H), 8.85 (d, J = 2.5 Hz, 1H), 8.30 (dd, J = fluoro-3- found 468.0 8.5,2.5 Hz, 1H), 8.20-7.98 (m, 2H), 7.84 (t, (trifluoromethyl)benzoyl]ami-(M + 1)+; J = 8.7 Hz, 1H), 7.59 (s, 1H), 7.48 (d, J = 2.6 no]pyridine-2-Retention time Hz, 1H), 7.37 (dd, J = 8.6, 2.6 Hz, 1H), 7.19 carboxamide(Method B): (d, J = 8.7 Hz, 1H), 6.72 (d, J = 8.9 Hz, 1H), 1.82 minutes2.14 (s, 3H). 219 5-[[6-(4-chloro-2- ESI-MS m/z 1H NMR (400 MHz,DMSO-d6) δ 11.48 (s, fluoro-phenoxy)-2- calc. 471.04092, 1H), 8.55 (d, J= 5.5 Hz, 1H), 8.28 (s, 1H), fluoro-3- found 472.0 8.10 (s, 1H), 7.93(s, 1H), 7.78 (s, 1H), 7.67 (trifluoromethyl)benzoyl]ami- (M + 1)+; (s,2H), 7.51 (d, J = 12.9 Hz, 1H), 7.17 (d, J = no]pyridine-2- Retentiontime 9.3 Hz, 1H), 7.08 (d, J = 8.7 Hz, 1H). carboxamide (Method B): 1.72minutes 220 5-[[6-(4-chloro-2- ESI-MS m/z 1H NMR (400 MHz, DMSO-d6) δ11.36 (s, methoxy-phenoxy)-2- calc. 483.06088, 1H), 8.87 (s, 1H), 8.30(d, J = 10.9 Hz, 1H), fluoro-3- found 484.0 8.14-7.94 (m, 2H), 7.79 (s,1H), 7.57 (s, 1H), (trifluoromethyl)benzoyl]ami- (M + 1)+; 7.36-7.21 (m,2H), 7.10 (d, J = 10.9 Hz, 1H), no]pyridine-2- Retention time 6.67 (d, J= 8.9 Hz, 1H), 3.78 (s, 3H). carboxamide (Method B): 1.75 minutes 2215-[[2-fluoro-6-[2- ESI-MS m/z 1H NMR (400 MHz, DMSO-d6) δ 11.45 (s,fluoro-4- calc. 521.0622, 1H), 8.84 (s, 1H), 8.28 (d, J = 11.0 Hz, 1H),(trifluoromethoxy)phenoxy]- found 522.0 8.13-7.98 (m, 2H), 7.90 (s, 1H),7.71 (d, J = 3- (M + 1)+; 13.4 Hz, 1H), 7.64-7.47 (m, 2H), 7.36 (d, J =(trifluoromethyl)benzoyl]ami- Retention time 9.0 Hz, 1H), 6.98 (d, J =8.8 Hz, 1H). no]pyridine-2- (Method B): carboxamide 1.73 minutes 2225-[[2-fluoro-6-[2- ESI-MS m/z 1H NMR (400 MHz, DMSO-d6) δ 11.42 (s,methyl-4- calc. 517.0873, 1H), 8.84 (s, 1H), 8.29 (d, J = 8.6 Hz, 1H),(trifluoromethoxy)phenoxy]- found 518.0 8.13-7.95 (m, 2H), 7.86 (s, 1H),7.57 (s, 1H), 3- (M + 1)+; 7.42 (s, 1H), 7.30 (d, J = 5.5 Hz, 2H), 6.75(d, (trifluoromethyl)benzoyl]ami- Retention time J = 8.8 Hz, 1H), 2.18(s, 3H). no]pyridine-2- (Method B): carboxamide 1.82 minutes 2235-[[6-[2-chloro-4- ESI-MS m/z 1H NMR (400 MHz, DMSO-d6) δ 11.42 (s,(trifluoromethoxy)phenoxy]- calc. 537.03265, 1H), 8.84 (s, 1H), 8.27 (d,J = 8.6 Hz, 1H), 2-fluoro-3- found 538.0 8.13-7.97 (m, 2H), 7.90 (s,1H), 7.82 (s, 1H), (trifluoromethyl)benzoyl]ami- (M + 1)+; 7.55 (d, J =21.6 Hz, 3H), 6.89 (d, J = 8.8 Hz, no]pyridine-2- Retention time 1H).carboxamide (Method B): 1.8 minutes

Example 495-[[6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(224)

Step 1:5-[[6-fluoro-2-methyl-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide

6-Fluoro-2-methyl-3-(trifluoromethyl)benzoic acid (2.95 g, 13.28 mmol)in anhydrous DCM (30 mL) under nitrogen was treated with DMF (50 μL,0.646 mmol), cooled in an ice bath and treated dropwise with oxalylchloride (2.2 mL, 25.22 mmol). The reaction was stirred for 10 minutesin the ice bath then the bath was removed. The clear solution wasstirred at RT for 1 hour. The mixture was concentrated to dryness underreduced pressure. The orange residue was dissolved in DCM (7.5 mL) andthe solution was added dropwise to a cold mixture of5-aminopyridine-2-carboxamide (2.2 g, 16.04 mmol) and DIEA (7 mL, 40.19mmol) in NMP (30 mL). The mixture was stirred at RT for 16 h. Themixture was concentrated under reduced pressure and the residue wasdiluted with EtOAc and water. The aqueous phase was extracted with EtOAc(1×75 mL). The combined organic layers were washed with brine (2×),dried over Na₂SO₄, filtered and concentrated to give white solid. Thecrude material was purified by silica chromatography eluting with agradient of methanol in DCM to give5-[[6-fluoro-2-methyl-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(3.14 g, 69%) as off-white solid. ESI-MS m/z calc. 341.07874, found342.2 (M+1)⁺; Retention time (Method B): 0.87 minutes. 1H NMR (400 MHz,DMSO-d6) δ 11.29 (s, 1H), 8.87 (d, J=2.4 Hz, 1H), 8.33 (dd, J=8.6, 2.5Hz, 1H), 8.15-8.00 (m, 2H), 7.92 (dd, J=9.0, 5.5 Hz, 1H), 7.58 (s, 1H),7.46 (t, J=8.7 Hz, 1H), 2.45 (d, J=1.8 Hz, 3H) ppm.

Step 2:5-[[6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(224)

5-[[6-Fluoro-2-methyl-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(75 mg, 0.220 mmol) and 3-fluoro-2-methoxy-4-(trifluoromethoxy)phenol(150 mg, 0.663 mmol) were dissolved in DMSO (200 L). To this clearsolution was added finely ground potassium carbonate (92 mg, 0.666mmol). The reaction mixture was stirred at 125° C. for 5 h. The mixturewas cooled to RT, filtered and purified by reverse phase HPLC (C18,1M99% CH₃CN/H₂O with 5 mM HCl) to give5-[[6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(11.3 mg, 9%) as an off-white solid. ESI-MS m/z calc. 547.09784, found548.2 (M+1)⁺; Retention time (Method B): 1.82 minutes. ¹H NMR (400 MHz,DMSO-d6) δ 11.22 (s, 1H), 8.87 (d, J=2.4 Hz, 1H), 8.32 (dd, J=8.6, 2.5Hz, 1H), 8.05 (d, 9=8.5 Hz, 1H), 8.01 (s, 1H), 7.76 (d, (=8.9 Hz, 1H),7.55 (sc, 1H), 7.42-7.33 (m, 1H), 7.13 (dd, ==9.4, 2.2 Hz, 1H), 6.90 (d,7=8.8 Hz, 1H), 3.84 (d, J=0.9 Hz, 3H), 2.46 (d, J=1.9 Hz, 3H) ppm.

The compounds set forth in Table 29 were prepared by methods analogousto the preparation of compound 224.

TABLE 29 Additional Compounds Prepared By Methods Analogous to Example49. Cmpd No. Compound Name LC/MS NMR (shifts in ppm) 225 5-[[2-methyl-3-ESI-MS m/z (trifluoromethyl)-6- calc. 469.08612, (2,3,4- found 470.2trifluorophenoxy)benzoyl]ami- (M + 1)+; no]pyridine-2- Retention timecarboxamide (Method B): 1.63 minutes 226 5-[[6-[2-cyclopropyl-4- ESI-MSm/z 1H NMR (400 MHz, DMSO-d6) δ 11.22 (s, (trifluoromethoxy)phenoxy]-calc. 539.128, 1H), 8.87 (dd, J = 2.5, 0.7 Hz, 1H), 8.33 2-methyl-3-found 540.1 (dd, J = 8.6, 2.5 Hz, 1H), 8.09-8.03 (m,(trifluoromethyl)benzoyl] (M + 1)+; 1H), 8.03-7.99 (m, 1H), 7.77 (d, J =8.9 amino]pyridine-2- Retention time Hz, 1H), 7.56 (s, 1H), 7.29-7.18(m, 2H), carboxamide (Method B): 6.98 (d, J = 2.5 Hz, 1H), 6.73 (d, J =8.8 Hz, 2.02 minutes 1H), 2.46 (d, J = 1.7 Hz, 3H), 1.99 (tt, J = 8.4,5.2 Hz, 1H), 0.91-0.80 (m, 2H), 0.74- 0.66 (m, 2H). 227 :5-[[6-(3,4-difluoro-2- ESI-MS m/z 1H NMR (400 MHz, DMSO-d6) δ 11.23 (s,methyl-phenoxy)-2- calc. 465.11118, 1H), 8.90-8.85 (m, 1H), 8.33 (dd, J= 8.6, methyl-3- found 466.1 2.5 Hz, 1H), 8.06 (d, J = 8.6 Hz, 1H), 8.02(trifluoromethyl)benzoyl] (M + 1)+; (s, 1H), 7.73 (d, J = 8.9 Hz, 1H),7.56 (s, amino]pyridine-2- Retention time 1H), 7.38 (q, J = 9.4 Hz, 1H),7.05-6.98 carboxamide (Method B): (m, 1H), 6.74 (d, J = 8.9 Hz, 1H),2.45 (d, 1.79 minutes J = 1.7 Hz, 3H), 2.10 (d, J = 2.1 Hz, 3H). 2285-[[6-(2,6-dimethoxy-4- ESI-MS m/z 1H NMR (400 MHz, DMSO-d6) δ 10.97 (s,methyl-phenoxy)-2- calc. 489.15115, 1H), 8.92 (d, J = 2.4 Hz, 1H), 8.38(dd, J = methyl-3- found 490.0 8.6, 2.5 Hz, 1H), 8.09-7.99 (m, 2H), 7.64(trifluoromethyl)benzoyl] (M + 1)+; (d, J = 8.9 Hz, 1H), 7.54 (d, J =2.7 Hz, 1H), amino]pyridine-2- Retention time 6.63 (s, 2H), 6.47 (d, J =8.8 Hz, 1H), 3.71 carboxamide (Method B): (s, 6H), 2.41 (d, J = 1.6 Hz,3H), 2.33 (s, 1.79 minutes 3H). 229 5-[[6-(4-chloro-2,6- ESI-MS m/z 1HNMR (400 MHz, DMSO-d6) δ 11.23 (s, dimethyl-phenoxy)-2- calc. 477.1067,1H), 8.89 (d, J = 2.4 Hz, 1H), 8.38 (dd, J = methyl-3- found 478.05 8.6,2.5 Hz, 1H), 8.06 (d, J = 8.6 Hz, 1H), (trifluoromethyl)benzoyl] (M +1)+; 8.01 (s, 1H), 7.67 (d, J = 8.9 Hz, 1H), 7.56 amino]pyridine-2-Retention time (d, J = 2.7 Hz, 1H), 7.29 (s, 2H), 6.42 (d, carboxamide(Method B): J = 8.8 Hz, 1H), 2.45 (d, J = 1.7 Hz, 3H), 1.97 minutes 2.07(s, 6H). 230 5-[[2-methyl-3- ESI-MS m/z (trifluoromethyl)-6- calc.469.08612, (2,4,6- found 469.95 trifluorophenoxy)benzoyl]ami- (M + 1)+;no]pyridine-2- Retention time carboxamide (Method B): 1.73 minutes 2315-[[6-(4-fluoro-2,3- ESI-MS m/z 1H NMR (400 MHz, DMSO-d6) δ 11.22 (s,dimethyl-phenoxy)-2- calc. 461.13626, 1H), 8.91-8.86 (m, 1H), 8.34 (dd,J = 8.6, methyl-3- found 462.0 2.5 Hz, 1H), 8.05 (d, J = 8.6 Hz, 1H),8.01 (trifluoromethyl)benzoyl] (M + 1)+; (d, J = 2.9 Hz, 1H), 7.70 (d, J= 8.9 Hz, 1H), amino]pyridine-2- Retention time 7.55 (s, 1H), 7.11carboxamide (Method B): (t, J = 9.0 Hz, 1H), 7.01 (dd, J = 8.9, 4.9 Hz,1.88 minutes 1H), 6.56 (d, J = 8.8 Hz, 1H), 2.44 (d, J = 1.8 Hz, 3H),2.17 (d, J = 2.1 Hz, 3H), 2.07 (s, 3H). 232 5-[[6-(4-fluoro-2- ESI-MSm/z 1H NMR (400 MHz, DMSO-d6) δ 11.14 (s, methoxy-phenoxy)-2- calc.463.1155, 1H), 8.91 (d, J = 2.4 Hz, 1H), 8.35 (dd, J = methyl-3- found464.0 8.6, 2.5 Hz, 1H), 8.09-7.99 (m, 2H), 7.69(trifluoromethyl)benzoyl] (M + 1)+; (d, J = 8.9 Hz, 1H), 7.55 (d, J =2.9 Hz, 1H), amino]pyridine-2- Retention time 7.23 (dd, J = 8.8, 5.9 Hz,1H), 7.15 (dd, J = carboxamide (Method B): 10.7, 2.9 Hz, 1H), 6.85 (td,J = 8.5, 2.9 Hz, 1.74 minutes 1H), 6.58 (d, J = 8.8 Hz, 1H), 3.76 (s,3H), 2.43 (d, J = 1.8 Hz, 3H). 233 5-[[6-(4-chloro-2-methyl- ESI-MS m/z1H NMR (400 MHz, DMSO-d6) δ 11.20 (s, phenoxy)-2-methyl-3- calc.463.09106, 1H), 8.87 (d, J = 2.3 Hz, 1H), 8.32 (dd, J =(trifluoromethyl)benzoyl] found 463.95 8.6, 2.5 Hz, 1H), 8.05 (d, J =8.6 Hz, 1H), amino]pyridine-2- (M + 1)+; 8.01 (s, 1H), 7.73 (d, J = 8.9Hz, 1H), 7.57- carboxamide Retention time 7.53 (m, 1H), 7.44 (d, J = 2.6Hz, 1H), (Method B): 7.34 (dd, J = 8.5, 2.7 Hz, 1H), 7.12 (d, J = 1.89minutes 8.6 Hz, 1H), 6.70 (d, J = 8.8 Hz, 1H), 2.45 (d, J = 1.7 Hz, 3H),2.12 (s, 3H). 234 5-[[6-(4-chloro-2-fluoro- ESI-MS m/z ¹H NMR (400 MHz,DMSO-d₆) δ 11.26 (s, phenoxy)-2-methyl-3- calc. 467.06598, 1H), 8.88 (d,J = 2.5 Hz, 1H), 8.32 (dd, J = (trifluoromethyl)benzoyl] found 468.18.5, 2.5 Hz, 1H), 8.16-7.95 (m, 2H), 7.77 amino]pyridine-2- (M + 1)+;(d, J = 8.9 Hz, 1H), 7.74-7.64 (m, 1H), carboxamide Retention time7.64-7.52 (m, 1H), 7.45-7.36 (m, 2H), (Method B): 6.89 (d, J = 8.8 Hz,1H), 2.43 (s, 3H). 1.76 minutes 235 5-[[6-(2-chloro-4- ESI-MS m/z 1H NMR(400 MHz, DMSO-d6) δ 11.14 (s, methoxy-phenoxy)-2- calc. 479.08597, 1H),8.90 (d, J = 2.4 Hz, 1H), 8.34 (dd, J = methyl-3- found 479.95 8.5, 2.5Hz, 1H), 8.05 (d, J = 8.5 Hz, 1H), (trifluoromethyl)benzoyl] (M + 1)+;8.01 (s, 1H), 7.69 (d, J = 8.9 Hz, 1H), 7.55 amino]pyridine-2- Retentiontime (s, 1H), 7.30 (d, J = 2.4 Hz, 1H), 7.21 (d, carboxamide (Method B):J = 8.5 Hz, 1H), 7.08 (dd, J = 8.5, 2.4 Hz, 1.82 minutes 1H), 6.63 (d, J= 8.8 Hz, 1H), 3.77 (s, 3H), 2.43 (d, J = 1.7 Hz, 3H). 2365-[[2-methyl-6-[2- ESI-MS m/z 1H NMR (400 MHz, DMSO-d6) δ 11.21 (s,methyl-4- calc. 513.1123, 1H), 8.89-8.84 (m, 1H), 8.31 (dd, J = 8.6,(trifluoromethoxy)phenoxy]- found 513.9 2.5 Hz, 1H), 8.08-7.98 (m, 2H),7.75 (d, J = 3- (M + 1)+; 8.9 Hz, 1H), 7.55 (d, J = 2.9 Hz, 1H), 7.39(trifluoromethyl)benzoyl] Retention time (d, J = 3.0 Hz, 1H), 7.29 (dd,J = 8.8, 2.9 amino]pyridine-2- (Method B): Hz, 1H), 7.21 (d, J = 8.9 Hz,1H), 6.73 (d, carboxamide 1.96 minutes J = 8.8 Hz, 1H), 2.45 (d, J = 1.7Hz, 3H), 2.17 (s, 3H).

Example 504-[[4-tert-butyl-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-benzoyl]amino]pyridine-2-carboxamide(237)

Step 1: methyl4-bromo-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-benzoate

A pressure vessel was charged with methyl4-bromo-2-fluoro-6-methyl-benzoate (5 g, 20.24 mmol),2-methoxy-4-(trifluoromethoxy)phenol (4.4 g, 21.14 mmol), Cs₂CO₃ (6.6 g,20.26 mmol) and DMF (61 mL). The vessel was sealed, the reaction mixturestirred at 100° C. for 16 hours, and the mixture was cooled to RT. Themixture was diluted with EtOAc, washed with brine (3×100 ml), and theorganic layer dried over Na₂SO₄, filtered and concentrated under reducedpressure. The residue was purified by silica gel chromatography with aEtOAc in hexanes gradient to give methyl4-bromo-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-benzoate (2.9g, 33%) as a clear oil. ¹H NMR (400 MHz, DMSO-d6) δ 7.29 (d, J=1.8 Hz,1H), 7.21 (d, J=2.7 Hz, 1H), 7.13 (d, J=8.8 Hz, 1H), 6.97 (ddd, J=8.9,2.7, 1.4 Hz, 1H), 6.68 (d, J=1.8 Hz, 1H), 3.80 (s, 6H), 2.27 (s, 3H)ppm.

Step 2: methyl4-tert-butyl-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-benzoate

To a solution of methyl4-bromo-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-benzoate (300mg, 0.689 mmol), 1,3-dicyclohexylimidazol-1-ium tetrafluoroborate (44mg, 0.137 mmol) and dichloronickel 1,2-dimethoxyethane (30 mg, 0.137mmol) in THF (20 mL) cooled to −15° C. was addedtert-butyl(chloro)magnesium (861 μL of 1 M, 0.861 mmol) in portions over5 minutes. The mixture was allowed to stir at −15 C for 30 minutes.Additional tert-butyl(chloro)magnesium (861 μL of 1 M, 0.8610 mmol) wasadded over 5 mins at −10° C. The reaction mixture was quenched withaqueous NH₄Cl and partitioned between ethyl acetate (30 ml) and water(30 ml). The aqueous layer was further extracted with EtOAc (50 mL). Thecombined organic layers were washed with brine, dried over magnesiumsulfate and concentrated under reduced pressure. The product waspurified by silica gel chromatography with a EtOAc in petroleum ethergradient to give methyl4-tert-butyl-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-benzoate(170 mg, 48%) as an oil. 1H NMR (500 MHz, Chloroform-d) δ 7.00 (dd,J=1.7, 0.8 Hz, 1H), 6.90-6.83 (m, 2H), 6.79-6.74 (m, 1H), 6.72 (d, J=1.9Hz, 1H), 3.88 (s, 3H), 3.81 (s, 3H), 2.42-2.37 (m, 3H), 1.25 (s, 9H)ppm. ESI-MS m/z calc. 412.14975, found 413.5 (M+1)⁺; Retention time(Method E): 3.21 minutes.

Step 3:4-tert-butyl-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-benzoicacid

Methyl4-tert-butyl-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-benzoate(225 mg, 0.546 mmol) was dissolved in ethanol (10 mL) and then aqueousLiOH (1000 μL of 2 M, 2.000 mmol) was added and the mixture heated to 60C for 1 h. An additional 2 mL aqueous LiOH (2M) was added and heatingwas continued for 5 h. The reaction was quenched with 2M HCl and themixture was concentrated under reduced pressure to give4-tert-butyl-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-benzoicacid (200 mg, 92%). 1H NMR (400 MHz, Chloroform-d) δ 7.28 (s, 1H),7.12-6.99 (m, 2H), 6.87 (s, 1H), 6.84-6.77 (m, 1H), 6.68 (dd, J=1.8, 0.6Hz, 1H), 3.85 (s, 3H), 2.55 (d, J=1.2 Hz, 1H), 2.55 (s, 2H), 1.23 (s,9H) ppm. ESI-MS m/z calc. 398.1341, found 397.2 (M−1)⁻; Retention time(Method D): 0.67 minutes.

Step 4:4-tert-butyl-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-benzamide

4-tert-Butyl-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-benzoicacid (200 mg, 0.502 mmol) was dissolved in DCM (10 mL) at 0° C., DMF (4μL, 0.0517 mmol) was added, followed by the dropwise addition of oxalylchloride (440 μL, 5.044 mmol). After 1 h, the mixture was concentratedunder reduced pressure, and the residue was taken up in DCM (10 mL) andadded dropwise to a stirring solution of NH₃ in dioxane (10 mL of 0.5 M,5.000 mmol). The mixture was stirred overnight and concentrated underreduced pressure. The residue was purified by silica gel chromatographywith a EtOAc in heptanes gradient to give4-tert-butyl-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-benzamide(35 mg, 18%). ¹H NMR (400 MHz, Chloroform-d) δ 6.99-6.83 (m, 2H),6.78-6.64 (m, 2H), 6.53 (dd, J=1.8, 0.6 Hz, 1H), 6.28 (s, 1H), 5.97 (s,1H), 3.73 (s, 3H), 2.39 (s, 3H), 1.67 (dt, J=13.6, 6.8 Hz, OH), 1.13 (s,9H) ppm. ESI-MS m/z calc. 397.1501, found 398.1 (M+1)⁺; Retention time(Method D): 0.97 minutes.

Step 5:4-[[4-tert-butyl-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-benzoyl]amino]pyridine-2-carboxamide(237)

4-tert-Butyl-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-benzamide(40 mg, 0.101 mmol), methyl 4-bromopyridine-2-carboxylate (26 mg, 0.120mmol),(5-diphenylphosphanyl-9,9-dimethyl-xanthen-4-yl)-diphenyl-phosphane (12mg, 0.0207 mmol) and cesium carbonate (75 mg, 0.230 mmol) were suspendedin dioxane (2 mL), then degassed with N₂ (flush and evacuation cycles).Then palladium(II) acetate (5 mg, 0.0223 mmol) was added and additionaldegassing was done. The mixture was heated to 100° C. The mixture wasconcentrated under reduced pressure and the residue dissolved in 5 mL 7Mammonia in MeOH and stirred overnight at 45° C. The material waspurified by reverse phase HPLC to give4-[[4-tert-butyl-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-benzoyl]amino]pyridine-2-carboxamide(0.5 mg, 1%). 1H NMR (400 MHz, Chloroform-d) δ 8.93 (s, 1H), 8.50 (d,J=5.6 Hz, 1H), 8.38 (s, 1H), 8.03 (s, 1H), 7.87 (s, 1H), 7.13-7.02 (m,2H), 6.93-6.80 (m, 3H), 6.69 (d, J=1.7 Hz, 1H), 3.90 (d, J=2.7 Hz, 3H),2.55 (s, 3H), 1.25 (s, 9H) ppm. ESI-MS m/z calc. 517.18243, found 518.1(M+1)⁺; Retention time (Method E): 1.02 minutes.

Example 515-tert-butyl-N-(2-carbamoyl-4-pyridyl)-3-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-2-carboxamide(238)

Step 1: 5-tert-butyl-3-fluoro-pyridine-2-carbonitrile

To a solution of 5-bromo-3-fluoro-pyridine-2-carbonitrile (500 mg, 2.488mmol), 1,3-diisopropylimidazol-1-ium chloride (approximately 188 mg,0.995 mmol) and dichloronickel 1,2-dimethoxyethane (approximately 219mg, 0.995 mmol) in THF (10 mL) cooled to −15° C. was addedtert-butylchloromagnesium (approximately 3.1 mL of 1 M, 3.1 mmol) inportions over 2-3 minutes. The mixture was allowed to stir at −15° C.for 30 minutes and then allowed to warm to RT. The mixture was cooled to−20° C. and additional tert-butylchloromagnesium (approximately 3.1 mLof 1 M, 3.1 mmol) was added. The reaction mixture was quenched withaqueous NH₄Cl and partitioned between ethyl acetate (30 ml) and water(30 ml). The aqueous layer was extracted with EtOAc (50 mL) and thecombined organic layers were washed with brine (1×20 mL), dried overmagnesium sulfate and concentrated under reduced pressure. The residuewas purified by silica gel chromatography with a EtOAc in petroleumether gradient to give 5-tert-butyl-3-fluoro-pyridine-2-carbonitrile (90mg, 19%) as an oil. 1H NMR (500 MHz, Chloroform-d) δ 8.61 (t, J=1.7 Hz,1H), 7.56 (dd, J=10.1, 1.9 Hz, 1H), 1.41 (s, 9H) ppm. ESI-MS m/z calc.178.09062, found 179.3 (M+1)⁺; Retention time (Method E): 2.26 minutes.

Step 2:5-tert-butyl-3-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-2-carbonitrile

2-Methoxy-4-(trifluoromethoxy)phenol (53.2 mg, 0.256 mmol),5-tert-butyl-3-fluoro-pyridine-2-carbonitrile (40 mg, 0.213 mmol) andCs₂CO₃ (approximately 104 mg, 0.320 mmol) were combined in DMF (456 μL)and sealed and heated at 70° C. for 1 hour. The reaction mixture wasallowed to cool to RT and partitioned between ethyl acetate (30 ml) andwater (30 ml). The aqueous layer was extracted with EtOAc (50 mL). Thecombined organic layers were washed with brine (1×20 mL), dried overmagnesium sulfate and concentrated under reduced pressure. The residuewas purified by silica gel chromatography eluting with a EtOAc inpetroleum ether gradient to give5-tert-butyl-3-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-2-carbonitrile(61 mg, 66%). ESI-MS m/z calc. 366.11914, found 367.5 (M+1)⁺; Retentiontime (Method E): 2.91 minutes.

Step 3:5-tert-butyl-3-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-2-carboxamide

To5-tert-butyl-3-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-2-carbonitrile(75 mg, 0.205 mmol) was added HCl (341 μL of 12 M, 4.09 mmol) and themixture stirred overnight at RT. To the mixture was added some ice andthen 5N NaOH until the pH was 8-9. The reaction mixture was partitionedbetween ethyl acetate (5 ml) and water (5 ml). The aqueous layer wasextracted with EtOAc (5 mL). The combined organic layers were washedwith brine, dried over magnesium sulfate and concentrated under reducedpressure and used as such in the next step.5-tert-Butyl-3-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-2-carboxamide(81 mg, 79%). ESI-MS m/z calc. 384.1297, found 385.5 (M+1)⁺; Retentiontime (Method E): 2.26 minutes.

Step 4: methyl4-[[5-tert-butyl-3-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-2-carbonyl]amino]pyridine-2-carboxylate

5-tert-Butyl-3-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-2-carboxamide(80 mg, 0.208 mmol), Xantphos (18 mg, 0.0311 mmol), cesium carbonate(149 mg, 0.457 mmol), Pd(OAc)₂ (7 mg, 0.0312 mmol) and methyl4-bromopyridine-2-carboxylate (58 mg, 0.269 mmol) were combined indioxane (3 mL) and heated at 100° C. for 3 hours. The reaction mixturewas allowed to cool to RT and was partitioned between ethyl acetate (30ml) and water (30 ml). The aqueous layer was extracted with EtOAc (50mL) and the combined organic layers were washed with brine (1×20 mL),dried over magnesium sulfate and concentrated under reduced pressure.The residue was purified by silica gel chromatography eluting with aEtOAc in petroleum ether gradient to give methyl4-[[5-tert-butyl-3-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-2-carbonyl]amino]pyridine-2-carboxylate(65 mg, 60%). ESI-MS m/z calc. 519.16174, found 520.5 (M+1)⁺; Retentiontime (Method D): 1.01 minutes

Step 5:5-tert-butyl-N-(2-carbamoyl-4-pyridyl)-3-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-2-carboxamide(238)

Methyl4-[[5-tert-butyl-3-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-2-carbonyl]amino]pyridine-2-carboxylate(70 mg, 0.1348 mmol) was added to ammonia (2.6 mL, 18.32 mmol) (7N inmethanol) and the mixture was stirred overnight at RT. The mixture wasconcentrated under reduced pressure to give5-tert-butyl-N-(2-carbamoyl-4-pyridyl)-3-[2-methoxy-4-(trifluoromethoxy)phenoxy]pyridine-2-carboxamide(35 mg, 41%). 1H NMR (500 MHz, DMSO-d6) δ 8.55 (d, J=1.9 Hz, 1H), 8.51(d, J=5.4 Hz, 1H), 8.44 (d, J=2.1 Hz, 1H), 8.06 (d, J=2.8 Hz, 1H), 7.90(dd, J=5.6, 2.1 Hz, 1H), 7.61 (d, J=2.8 Hz, 1H), 7.30 (d, J=1.9 Hz, 1H),7.24-7.16 (m, 2H), 7.13-7.05 (m, 2H), 6.99-6.87 (m, 1H), 3.79 (s, 3H),1.29 (s, 7H) ppm. ESI-MS m/z calc. 504.16205, found 505.6 (M+1)⁺;Retention time (Method E): 3.34 minutes.

Example 524-[[6-[2-chloro-4-(trifluoromethoxy)phenoxy]-2,2-difluoro-4-methyl-1,3-benzodioxole-5-carbonyl]amino]pyridine-2-carboxamide(239)

Step 1: 6-bromo-2,2-difluoro-4-methyl-1,3-benzodioxole-5-carboxylic acid

To 2,2-difluoro-4-methyl-1,3-benzodioxole-5-carboxylic acid (2.5 g,11.57 mmol) was added palladium(II) acetate (610 mg, 2.717 mmol),tetramethylammonium bromide (2.9 g, 18.83 mmol),(acetyloxy)(phenyl)-lambda3-iodanyl acetate (7.9 g, 24.53 mmol), iodine(6.5 g, 25.61 mmol) and DCE (25 mL) and the reaction was stirred at 60°C. for 16 h. Additional palladium(II) acetate (610 mg, 2.717 mmol),tetramethylammonium bromide (2.9 g, 18.83 mmol),(acetyloxy)(phenyl)-lambda3-iodanyl acetate (7.9 g, 24.53 mmol), andiodine (6.5 g, 25.61 mmol) were added to the reaction and it was andheated at 60° C. for 68 h. The reaction was allowed to cool to RT andwas acidified with 1 M HCl. A solution of sodium bisulfite (˜ 40%) wasadded to the mixture and it was extracted with DCM (3×). The combinedorganic layers were dried over Na₂SO₄, filtered and the solvent wasevaporated under reduced pressure. The crude product was dissolved inDMSO, filtered and purified by reverse phase HPLC (C18 column, gradientof CH₃CN and water (5 mM HCl)) to yield6-bromo-2,2-difluoro-4-methyl-1,3-benzodioxole-5-carboxylic acid (1.3118g, 38%) as a white solid. ESI-MS m/z calc. 293.93393, found 295.0(M+1)⁺; Retention time (Method A): 0.56 minutes.

Step 2:6-[2-chloro-4-(trifluoromethoxy)phenoxy]-2,2-difluoro-4-methyl-1,3-benzodioxole-5-carboxylicacid

A flask containing6-bromo-2,2-difluoro-4-methyl-1,3-benzodioxole-5-carboxylic acid (1.3 g,4.406 mmol), toluene (30 mL) and a stirrer bar was flushed with N₂ for10 min. 2-Chloro-4-(trifluoromethoxy)phenol (1.01 g, 4.752 mmol) andcesium carbonate (3.04 g, 9.33 mmol) were added to the mixture and itwas flushed with N₂ for 10 min. Copper iodide (186 mg, 0.977 mmol) wasadded and the mixture was flushed with N₂ for 10 min. The reaction wasstirred at 80° C. with vigorous stirring under N₂ for 14 h. The mixturewas allowed to cool to RT, and then diluted with ethyl acetate andwater, and acidified with 1 M HCl. The layers were separated and theaqueous layer was extracted with EtOAc (3×). The combined organic layerswere filtered and the filtrate was washed with water and brine, driedover sodium sulfate, filtered through a plug of celite and concentratedunder reduced pressure. The crude product was dissolved in DMSO,filtered and purified by reverse phase HPLC (C18 column, gradient ofCH₃CN and water (5 mM HCl)) to yield6-[2-chloro-4-(trifluoromethoxy)phenoxy]-2,2-difluoro-4-methyl-1,3-benzodioxole-5-carboxylicacid (482.5 mg, 26%) as an off-white solid. ESI-MS m/z calc. 425.99295,found 427.1 (M+1)⁺; Retention time (Method A): 0.77 minutes.

Step 3:6-[2-chloro-4-(trifluoromethoxy)phenoxy]-2,2-difluoro-4-methyl-1,3-benzodioxole-5-carbonylchloride

To6-[2-chloro-4-(trifluoromethoxy)phenoxy]-2,2-difluoro-4-methyl-1,3-benzodioxole-5-carboxylicacid (203 mg, 0.476 mmol) and DMF (15 μL, 0.194 mmol) in DCM (2 mL) at0° C. was added oxalyl chloride (120 μL, 1.376 mmol) dropwise under a N₂atmosphere. The ice bath was removed after 10 min and the reaction wasstirred at RT for 1.5 h. The solvent was evaporated under reducedpressure to afford6-[2-chloro-4-(trifluoromethoxy)phenoxy]-2,2-difluoro-4-methyl-1,3-benzodioxole-5-carbonylchloride, which was used directly in the next step.

Step 4:4-[[6-[2-chloro-4-(trifluoromethoxy)phenoxy]-2,2-difluoro-4-methyl-1,3-benzodioxole-5-carbonyl]amino]pyridine-2-carboxamide(239)

To 4-aminopyridine-2-carboxamide (approximately 41.9 mg, 0.306 mmol) inNMP (500 μL), and DIEA (133 μL, 0.764 mmol) at 0° C. was added asolution of the above acid chloride (68 mg, 0.153 mmol) in NMP (500 μL)slowly. The reaction was stirred at RT for 2.5 h and at 75° C. for 1 h.The crude product was filtered and purified by reverse phase HPLC (C18column, gradient of CH₃CN and water (5 mM HCl)) to yield4-[[6-[2-chloro-4-(trifluoromethoxy)phenoxy]-2,2-difluoro-4-methyl-1,3-benzodioxole-5-carbonyl]amino]pyridine-2-carboxamide(17.1 mg, 21%). ESI-MS m/z calc. 545.0413, found 546.1 (M+1)⁺; Retentiontime (Method C): 2.72 minutes. 1H NMR (400 MHz, DMSO-d6) δ 11.16 (s,1H), 8.51 (d, J=5.5 Hz, 1H), 8.27 (d, J=2.1 Hz, 1H), 8.09 (d, J=2.8 Hz,1H), 7.75 (dd, J=5.5, 2.2 Hz, 1H), 7.69-7.60 (m, 2H), 7.40-7.34 (m, 1H),7.30 (s, 1H), 7.19 (d, J=9.1 Hz, 1H), 2.31 (s, 3H) ppm.

The compounds set forth in Table 30 were prepared by methods analogousto the preparation of compound 239.

TABLE 30 Additional Compounds Prepared By Methods Analogous to Example52. Cmpd No. Compound Name LC/MS NMR (shifts in ppm) 2405-[[6-[2-chloro-4- ESI-MS m/z 1H NMR (400 MHz, DMSO-d6) δ 11.04(trifluoromethoxy)phenoxy]- calc. 545.0413, (s, 1H), 8.77 (dd, J = 2.5,0.7 Hz, 1H), 2,2-difluoro-4-methyl- found 546.1 8.18 (dd, J = 8.6, 2.4Hz, 1H), 8.06-7.94 1,3-benzodioxole-5- (M + 1)+; (m, 2H), 7.72-7.60 (m,1H), 7.59-7.49 carbonyl]amino]pyridine- Retention time (m, 1H),7.41-7.28 (m, 2H), 7.16 (d, J = 2-carboxamide (Method C): 9.1 Hz, 1H),2.34-2.27 (m, 3H). 2.72 minutes

Example 534-[[2-[2-chloro-4-(trifluoromethoxy)phenoxy]-6-methyl-4-(trifluoromethoxy)benzoyl]amino]pyridine-2-carboxamide(241)

Step 1: 2-iodo-6-methyl-4-(trifluoromethoxy)benzoic acid

2-Methyl-4-(trifluoromethoxy)benzoic acid (7.0 g, 31.80 mmol),(diacetoxyiodo)benzene (12.3 g, 38.19 mmol), I₂ (9.7 g, 38.22 mmol) andPd(OAc)₂ (380 mg, 1.693 mmol) were combined in DMF (100 mL) under N₂.The mixture was de-gassed (×3 vacuum-N₂ flush cycles). N₂ was replacedwith Ar and the mixture was stirred overnight at 105° C. The mixture wascooled to RT and partitioned between EtOAc and saturated sodiumthiosulfate solution. The aqueous phase was extracted with EtOAc (2×)and the combined organics were dried (Na₂SO₄), filtered and concentratedunder reduced pressure. The residue was purified by silica gelchromatography eluting with an EtOAc-heptane gradient to give2-iodo-6-methyl-4-(trifluoromethoxy)benzoic acid (3.57 g, 30%) as awhite solid. 1H NMR (400 MHz, DMSO-d6) δ 13.75 (s, 1H), 7.71 (dt, J=2.5,0.9 Hz, 1H), 7.37 (ddt, J=3.1, 2.2, 1.1 Hz, 1H), 2.51 (p, J=1.8 Hz, 3H)ppm. ESI-MS m/z calc. 345.93137, found 345.0 (M−1)⁻; Retention time(Method E): 0.84 minutes.

Step 2:2-[2-chloro-4-(trifluoromethoxy)phenoxy]-6-methyl-4-(trifluoromethoxy)benzoicacid

2-Iodo-6-methyl-4-(trifluoromethoxy)benzoic acid (1.0 g, 2.688 mmol) and2-chloro-4-(trifluoromethoxy)phenol (686 mg, 3.227 mmol) were dissolvedin toluene (20 mL) and Cs₂CO₃ (2.3 g, 7.06 mmol) was added. The mixturewas de-gassed (×2 vacuum-N₂ flush cycles) andtetrakis(acetonitrile)copper(I) hexafluorophosphate (246 mg, 0.660 mmol)was added. The mixture was de-gassed and heated at reflux overnight. Themixture was cooled to RT and partitioned between EtOAc and 2M HCl. Theaqueous phase was extracted with EtOAc and the combined organics weredried (Na₂SO₄), filtered and concentrated under reduced pressure. Theresidue was purified by silica gel chromatography eluting with anEtOAc-heptane gradient to give2-[2-chloro-4-(trifluoromethoxy)phenoxy]-6-methyl-4-(trifluoromethoxy)benzoicacid (433 mg, 37%). 1H NMR (400 MHz, DMSO-d6) δ 13.55 (s, 1H), 7.77 (dd,J=2.9, 0.8 Hz, 1H), 7.41 (ddq, J=9.0, 3.0, 1.0 Hz, 1H), 7.20 (dt, J=2.3,1.1 Hz, 1H), 7.13 (d, J=9.0 Hz, 1H), 6.84 (d, J=2.1 Hz, 1H), 2.39 (s,3H) ppm. ESI-MS m/z calc. 430.00427, found 431.0 (M+1)⁺; 429.0 (M−1)⁻;Retention time (Method D): 0.68 minutes.

Step 3:2-[2-chloro-4-(trifluoromethoxy)phenoxy]-6-methyl-4-(trifluoromethoxy)benzamide

2-[2-Chloro-4-(trifluoromethoxy)phenoxy]-6-methyl-4-(trifluoromethoxy)benzoicacid (200 mg, 0.4644 mmol) was dissolved in DCM (3 mL) under N₂ and thesolution cooled in an ice bath. Oxalyl chloride (120 μL, 1.376 mmol) wasadded dropwise with stirring, followed by the addition of DMF (3 μL,0.0387 mmol). After stirring for 35 minutes, the mixture wasconcentrated and the residue re-dissolved in DCM (3 mL) under N₂.Ammonia in dioxane (10 mL of 0.5 M, 5.000 mmol) was added with coolingin an ice bath, and after 5 minutes the ice bath was removed and theresulting cloudy solution stirred for 30 minutes. The mixture wasconcentrated under reduced pressure and the residue partitioned wasbetween EtOAc and water. The aqueous phase was extracted with EtOAc andthe combined organics were washed with brine, dried (Na₂SO₄), filteredand concentrated under reduced pressure to give2-[2-chloro-4-(trifluoromethoxy)phenoxy]-6-methyl-4-(trifluoromethoxy)benzamide(153 mg, 73%) which was taken directly on to the next reaction withoutfurther purification. 1H NMR (400 MHz, DMSO-d6) δ 7.91 (s, 1H), 7.75(dt, J=2.8, 0.8 Hz, 1H), 7.65 (s, 1H), 7.42 (ddt, J=9.0, 2.9, 1.1 Hz,1H), 7.24-7.07 (m, 2H), 6.81-6.68 (m, 1H), 2.41-2.34 (m, 3H) ppm. ESI-MSm/z calc. 429.02026, found 430.0 (M+1)⁺; 428.0 (M−1)⁻; Retention time(Method D): 0.97 minutes.

Step 4:4-[[2-[2-chloro-4-(trifluoromethoxy)phenoxy]-6-methyl-4-(trifluoromethoxy)benzoyl]amino]pyridine-2-carboxamide(241)

2-[2-Chloro-4-(trifluoromethoxy)phenoxy]-6-methyl-4-(trifluoromethoxy)benzamide(153 mg, 0.338 mmol), methyl 4-bromopyridine-2-carboxylate (90 mg, 0.417mmol), Xantphos (40 mg, 0.0691 mmol) and Cs₂CO₃ (245 mg, 0.752 mmol)were combined in dioxane (4 mL) under N₂. The mixture was de-gassed (×2vacuum-N₂ flush cycles) and Pd(OAc)₂ (14 mg, 0.0624 mmol) was added. Themixture was de-gassed (×2 cycles) then heated at 100° C. for 3 hours.The mixture was cooled to RT and partitioned between EtOAc and water.The aqueous phase was extracted with EtOAc and the combined organicswashed with brine, dried (Na₂SO₄), filtered and concentrated underreduced pressure. The residue was stirred with ammonia in MeOH (5 mL of7 M) under N₂ over the weekend. The mixture was concentrated and theresidue taken up in DMSO, filtered and purified by HPLC. The resultingwhite solid was only ˜90% pure and was taken up in MeOH and passedthrough SPE bicarbonate cartridges. The filtrate was concentrated andthe residue further purified by silica gel chromatography eluting withan EtOAc-heptane gradient. This material was also ˜90% pure. A finalpurification by HPLC was carried out to give4-[[2-[2-chloro-4-(trifluoromethoxy)phenoxy]-6-methyl-4-(trifluoromethoxy)benzoyl]amino]pyridine-2-carboxamide(34.13 mg, 18%) as a white solid. 1H NMR (500 MHz, DMSO-d6) δ 11.17 (s,1H), 8.51 (d, J=5.5 Hz, 1H), 8.31 (d, J=2.1 Hz, 1H), 8.07 (s, 1H), 7.79(dd, J=5.5, 2.2 Hz, 1H), 7.71 (d, J=2.9 Hz, 1H), 7.63 (s, 1H), 7.49-7.40(m, 1H), 7.30 (d, J=9.0 Hz, 1H), 7.26 (s, 1H), 6.85 (s, 1H), 2.40 (s,3H) ppm. ESI-MS m/z calc. 549.0526, found 550.0 (M+1)⁺; 548.0 (M−1)⁻;Retention time (Method E): 3.46 minutes.

Example 544-[[2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-4-(trifluoromethoxy)benzoyl]amino]pyridine-2-carboxamide(242)

Step 1:2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-4-(trifluoromethoxy)benzoicacid

2-Iodo-6-methyl-4-(trifluoromethoxy)benzoic acid (1.0 g, 2.312 mmol) and2-methoxy-4-(trifluoromethoxy)phenol (600 mg, 2.883 mmol) were dissolvedin toluene (20 mL) and Cs₂CO₃ (1.9 g, 5.831 mmol) was added. The mixturewas de-gassed (×2 vacuum-N₂ flush cycles) andtetrakis(acetonitrile)copper(I) hexafluorophosphate (212 mg, 0.5688mmol) was added. The mixture was de-gassed and heated at refluxovernight. The mixture was cooled to RT and partitioned between EtOAcand 2M HCl. The aqueous phase was extracted with EtOAc and the combinedorganics were dried (Na₂SO₄), filtered and concentrated under reducedpressure. The residue was purified by silica gel chromatography using anEtOAc-heptane gradient to give2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-4-(trifluoromethoxy)benzoicacid (651 mg, 66%). 1H NMR (400 MHz, DMSO-d6) δ 13.44 (s, 1H), 7.22 (d,J=2.8 Hz, 1H), 7.13 (d, J=8.8 Hz, 1H), 7.05 (dt, J=2.2, 1.0 Hz, 1H),6.99 (ddq, J=8.8, 2.4, 1.2 Hz, 1H), 6.43 (dt, J=2.2, 0.9 Hz, 1H), 3.80(s, 3H), 2.36 (s, 3H) ppm. ESI-MS m/z calc. 426.0538, found 427.0(M+1)⁺; 425.0 (M−1)⁻; Retention time (Method D): 0.67 minutes.

Step 2:2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-4-(trifluoromethoxy)benzamide

2-[2-Methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-4-(trifluoromethoxy)benzoicacid (200 mg, 0.4692 mmol) was dissolved in DCM (3 mL) under N₂, thesolution was cooled in an ice bath, and oxalyl chloride (120 μL, 1.376mmol) was added dropwise with stirring followed by the addition of DMF(3 μL, 0.03874 mmol). After stirring for 35 minutes the mixture wasconcentrated and the residue dissolved in DCM (3 mL) under N₂. Ammoniain dioxane (10 mL of 0.5 M, 5.000 mmol) was added with cooling in an icebath. After 5 minutes the ice bath was removed and the resulting cloudysolution stirred for 30 minutes. The mixture was concentrated underreduced pressure and the residue was partitioned between EtOAc andwater. The aqueous phase was extracted with EtOAc and the combinedorganics were washed with brine, dried (Na₂SO₄), filtered andconcentrated under reduced pressure to give2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-4-(trifluoromethoxy)benzamide(184 mg, 83%) which was taken directly on to the next step withoutfurther purification. 1H NMR (400 MHz, DMSO-d6) δ 7.84 (s, 1H), 7.61 (s,1H), 7.21 (d, J=2.7 Hz, 1H), 7.16 (d, J=8.8 Hz, 1H), 7.04-6.97 (m, 2H),6.39-6.35 (m, 1H), 3.81 (s, 3H), 2.34 (d, J=0.7 Hz, 3H) ppm. ESI-MS m/zcalc. 425.0698, found 426.0 (M+1)⁺; 424.0 (M−1)⁻; Retention time (MethodD): 0.94 minutes.

Step 3:4-[[2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-4-(trifluoromethoxy)benzoyl]amino]pyridine-2-carboxamide(242)

2-[2-Methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-4-(trifluoromethoxy)benzamide(184 mg, 0.389 mmol), methyl 4-bromopyridine-2-carboxylate (102 mg,0.472 mmol), Xantphos (45 mg, 0.0777 mmol) and Cs₂CO₃ (280 mg, 0.859mmol) were combined in dioxane (5 mL) under N₂. The mixture wasde-gassed (×2 vacuum-N₂ flush cycles) and Pd(OAc)₂ (15 mg, 0.0661 mmol)added. The mixture was de-gassed (×2 cycles) then heated at 100° C. for90 minutes. The mixture was cooled to RT and partitioned between EtOAcand water. The aqueous phase was extracted with EtOAc and the combinedorganics were washed with brine, dried (Na₂SO₄), filtered andconcentrated under reduced pressure. The residue was stirred withammonia in MeOH (5 mL of 7 M) under N₂ over the weekend. The mixture wasconcentrated and the residue taken up in DMSO, filtered and purified byHPLC. The resulting white solid was only ˜90% pure by UV. Furtherpurification by silica gel chromatography using an EtOAc-heptane elutiongave4-[[2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-4-(trifluoromethoxy)benzoyl]amino]pyridine-2-carboxamide(63.50 mg, 29%) as a white solid. 1H NMR (500 MHz, DMSO-d6) δ 11.13 (s,1H), 8.52 (d, J=5.6 Hz, 1H), 8.35 (d, J=2.1 Hz, 1H), 8.07 (d, J=2.8 Hz,1H), 7.84 (dd, J=5.6, 2.2 Hz, 1H), 7.63 (d, J=2.8 Hz, 1H), 7.26 (d,J=8.8 Hz, 1H), 7.19 (d, J=2.7 Hz, 1H), 7.12 (s, 1H), 7.04-6.97 (m, 1H),6.48 (s, 1H), 3.77 (s, 3H), 2.38 (s, 3H) ppm. ESI-MS m/z calc. 545.1022,found 546.0 (M+1)⁺; 544.0 (M−1)⁻; Retention time (Method E): 3.38minutes.

Example 555-[[2-[2-chloro-4-(trifluoromethoxy)phenoxy]-6-methyl-4-(trifluoromethoxy)benzoyl]amino]pyridine-2-carboxamide(243)

Step 1: methyl 5-bromopyridine-2-carboxylate

A solution of 5-bromopyridine-2-carboxylic acid (10 g, 49.5 mmol) inmethanol (165 mL) was treated with sulfuric acid (4.9 g, 2.6 mL, 49.5mmol) and refluxed overnight. The solution was concentrated and theresulting product partitioned between saturated aqueous sodiumbicarbonate and ethyl acetate. The organic layer was separated and theaqueous layer extracted with additional ethyl acetate (2×). The combinedorganic layers were dried and concentrated to provide methyl5-bromopyridine-2-carboxylate (10 g).

Step 2:5-[[2-[2-chloro-4-(trifluoromethoxy)phenoxy]-6-methyl-4-(trifluoromethoxy)benzoyl]amino]pyridine-2-carboxamide(243)

2-[2-Chloro-4-(trifluoromethoxy)phenoxy]-6-methyl-4-(trifluoromethoxy)benzamide(179 mg, 0.354 mmol), methyl 5-bromopyridine-2-carboxylate (92 mg, 0.43mmol), Xantphos (41 mg, 0.07 mmol) and Cs₂CO₃ (255 mg, 0.783 mmol) werecombined in dioxane (4 mL) under nitrogen. The mixture was degassed(2×vacuum-nitrogen cycles) and Pd(OAc)₂ (13 mg, 0.058 mmol) added. Themixture was again degassed (2×vacuum-nitrogen cycles) then heated at100° C. for 2 hours. The reaction mixture was cooled to RT andpartitioned between ethyl acetate and water. The aqueous phase wasextracted with additional ethyl acetate and the combined organics washedwith brine, dried over Na₂SO₄, filtered and concentrated under reducedpressure. The residue was stirred with ammonia in methanol (5 mL, 7 M)under nitrogen overnight. The reaction mixture was concentrated andpurified sequentially by silica gel chromatography (ethylacetate-heptane gradient) and HPLC (acetonitrile/water gradient withammonia modifier) to provide5-[[2-[2-chloro-4-(trifluoromethoxy)phenoxy]-6-methyl-4-(trifluoromethoxy)benzoyl]amino]pyridine-2-carboxamide(23 mg, 12%). ESI-MS m/z calc. 549.05, found 550.0 (M+1)⁺; 548.0 (M−1)⁻;Retention time (Method E): 3.41 minutes. ¹H NMR (500 MHz, DMSO-d6) δ11.07 (s, 1H), 8.82 (d, J=2.5 Hz, 1H), 8.23 (dd, J=8.7, 2.4 Hz, 1H),8.02 (d, J=8.6 Hz, 1H), 7.99 (s, 1H), 7.71 (d, J=2.8 Hz, 1H), 7.53 (s,1H), 7.44 (d, J=9.4 Hz, 1H), 7.28 (d, J=9.0 Hz, 2H), 6.89 (s, 1H), 2.41(s, 3H) ppm.

Example 564-[[3-(difluoromethyl)-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzoyl]amino]pyridine-2-carboxamide(244)

Step 1:3-bromo-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzoic acid

To a pressure flask was added 3-bromo-6-iodo-2-methyl-benzoic acid (1000mg, 2.933 mmol), 2-methoxy-4-(trifluoromethoxy)phenol (611 mg, 2.94mmol), Cs₂CO₃ (1.44 g, 4.42 mmol), toluene (18 mL) and a stir bar. Thereaction mixture was bubbled with nitrogen for 10 minutes, then copper(I) iodide (563 mg, 2.96 mmol) added. The flask was flushed withnitrogen, capped, and heated at 100° C. with vigorous stirring for 16hours. The mixture was allowed to cool, and then diluted with ethylacetate and water. The water layer was acidified with 1 M HCl and theproduct extracted into ethyl acetate (3×). The combined organics weredried over Na₂SO₄, filtered and concentrated under reduced pressure.Medium pressure reverse phase chromatography (C18, CH₃CN/water (5 mMHCl) gradient) provided3-bromo-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzoic acid(455 mg, 37%). ¹H NMR (400 MHz, Chloroform-d) δ 7.47 (d, J=8.8 Hz, 1H),7.15-7.06 (m, 1H), 6.85 (ddd, J=6.9, 2.4, 1.1 Hz, 2H), 6.46 (dd, J=8.9,0.7 Hz, 1H), 3.81 (s, 3H), 2.52 (s, 3H) ppm.

Step 2: methyl3-bromo-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzoate

3-Bromo-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzoic acid(450 mg, 1.07 mmol) was dissolved in a mixture of dichloromethane (7 mL)and methanol (1.1 mL, 27.16 mmol) and cooled in an ice bath undernitrogen. Diazomethyl(trimethyl)silane in hexanes (1.4 mL of 2 M, 2.8mmol) was added dropwise and the reaction was stirred on ice for 15minutes. A solution of acetic acid in methanol (1:5) was added dropwiseto quench excess reagent (removal of yellow color and bubbling). Thereaction was concentrated and the crude material was purified by silicagel chromatography (ethyl acetate/hexanes gradient) to provide methyl3-bromo-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzoate (423mg, 91%) as a clear oil. ESI-MS m/z calc. 434.00, found 435.1 (M+1)⁺;Retention time (Method A): 0.82 minutes. ¹H NMR (400 MHz, Chloroform-d)δ 7.43 (d, J=8.8 Hz, 1H), 6.99 (d, J=8.7 Hz, 1H), 6.83 (d, J=2.7 Hz,1H), 6.81-6.76 (m, 1H), 6.44 (d, J=8.8, 0.7 Hz, 1H), 3.90 (s, 3H), 3.81(s, 3H), 2.38 (s, 3H) ppm.

Step 3: methyl3-formyl-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzoate

Methyl3-bromo-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzoate (260mg, 0.597 mmol) was dissolved in THF (1 mL) and cooled in an ice bathunder nitrogen. Isopropylmagnesium chloride in THF (150 μL of 2 M, 0.3mmol) was added and the reaction mixture was stirred for 5 minutes.n-Butyllithium (240 μL of 2.5 M, 0.6000 mmol) was then added and thereaction was stirred an additional 10 minutes. DMF (100 μL, 1.29 mmol)was added dropwise and the reaction was stirred for 30 minutes. Themixture was quenched with a saturated citric acid solution and extractedwith ethyl acetate. The organics were washed with brine, dried overNa₂SO₄, filtered and concentrated. Silica gel chromatography (ethylacetate/hexanes gradient) provided methyl3-formyl-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzoate(103 mg, 45%) as a clear oil. ESI-MS m/z calc. 384.08, found 385.0(M+1)⁺; Retention time (Method A): 0.7 minutes. ¹H NMR (400 MHz,Chloroform-d) δ 10.18 (s, 1H), 7.73 (d, J=8.7 Hz, 1H), 7.13-7.08 (m,1H), 6.88-6.82 (m, 2H), 6.56 (d, J=8.7 Hz, 1H), 3.96 (s, 3H), 3.79 (s,3H), 2.65 (s, 3H) ppm.

Step 4: methyl3-(difluoromethyl)-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzoate

Methyl3-formyl-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzoate(100 mg, 0.260 mmol) was dissolved in dichloromethane (1 mL) andbis(2-methoxyethyl)aminosulfur trifluoride (240 μL, 1.30 mmol) was addeddropwise and the solution was allowed to stir at RT for 3 hours. Thereaction was cooled in an ice bath and a saturated solution of sodiumbicarbonate was added dropwise until bubbling had ceased. The reactionmixture was extracted with dichloromethane. The organic phase was washedwith brine, dried over Na₂SO₄ and evaporated. Silica gel chromatography(ethyl acetate/hexanes gradient) provided methyl3-(difluoromethyl)-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzoate(83 mg, 79%) as a clear oil. ¹H NMR (400 MHz, Chloroform-d) δ 7.41 (d,J=8.6 Hz, 1H), 7.05 (d, J=8.6 Hz, 1H), 6.85-6.79 (m, 2H), 6.72 (t,J=55.4 Hz, 1H), 6.55 (d, J=8.7 Hz, 1H), 3.93 (s, 3H), 3.80 (s, 3H), 2.39(d, J=1.3 Hz, 3H) ppm.

Step 5:3-(difluoromethyl)-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzoicacid

Methyl3-(difluoromethyl)-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzoate(80 mg, 0.20 mmol) and NaOH (500 mg, 12.5 mmol) were combined in amixture of DMF (5 mL)/water (5 mL) and heated in a sealed vial at 120°C. for 16 hours. The reaction was acidified with conc. HCl to a pH of ˜1and extracted with ethyl acetate (3×10 mL). The combined organics werewashed with brine, dried over Na₂SO₄, filtered and concentrated. HPLCpurification (CH₃CN/water (5 mM HCl) gradient) provided3-(difluoromethyl)-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzoicacid (39.6 mg, 51%). ESI-MS m/z calc. 392.07, found 393.3 (M+1)⁺;Retention time (Method A): 0.69 minutes.

Step 6:4-[[3-(difluoromethyl)-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzoyl]amino]pyridine-2-carboxamide(244)

3-(Difluoromethyl)-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzoicacid (36.6 mg, 0.093 mmol) and oxalyl chloride (50 μL, 0.57 mmol) werecombined in dichloromethane (800 μL) and a drop of DMF was added. Thereaction was stirred at 50° C. for 30 minutes then evaporated to drynessto provide the corresponding acid chloride. The acid chloride wasdissolved in dichloromethane (0.5 mL) and added to a solution of4-aminopyridine-2-carboxamide (14 mg, 0.10 mmol) and DIEA (50 μL, 0.29mmol) in NMP (0.5 mL). The reaction mixture was stirred at RT for 24hours. The mixture was filtered and purified by HPLC (CH₃CN/water (5 mMHCl) gradient) to provide4-[[3-(difluoromethyl)-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzoyl]amino]pyridine-2-carboxamide(6.4 mg, 13%). ESI-MS m/z calc. 511.12, found 512.0 (M+1)⁺; Retentiontime (Method B): 1.64 minutes. ¹H NMR (400 MHz, DMSO-d6) δ 11.23 (s,1H), 8.53 (d, J=5.5 Hz, 1H), 8.39 (d, J=2.1 Hz, 1H), 8.12 (s, 1H), 7.87(dd, J=5.5, 2.2 Hz, 1H), 7.67 (s, 1H), 7.55 (d, J=8.8 Hz, 1H), 7.26 (d,J=8.8 Hz, 1H), 7.20 (t, J=55 Hz, 1H), 7.20 (s, 1H), 7.03-6.98 (m, 1H),6.61 (d, J=8.6 Hz, 1H), 3.77 (s, 3H), 2.39 (s, 3H) ppm.

Example 575-[[2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-4-(trifluoromethoxy)benzoyl]amino]pyridine-2-carboxamide(245)

Step 1:2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-4-(trifluoromethoxy)benzoicacid

2-Iodo-6-methyl-4-(trifluoromethoxy)benzoic acid (1.0 g, 2.3 mmol) and2-methoxy-4-(trifluoromethoxy)phenol (600 mg, 2.88 mmol) were dissolvedin toluene (20 mL) and Cs₂CO₃ (1.9 g, 5.8 mmol) added. The mixture wasdegassed (2×vacuum-nitrogen cycles) and tetrakis(acetonitrile) copper(I)hexafluorophosphate (212 mg, 0.569 mmol) added. The mixture was againdegassed and heated at reflux overnight. The reaction mixture was cooledto RT and partitioned between ethyl acetate and 2 M HCl. The aqueousphase was extracted with additional ethyl acetate and the combinedorganics dried over Na₂SO₄, filtered and concentrated under reducedpressure. Silica gel chromatography (ethyl acetate/heptane gradient)provided2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-4-(trifluoromethoxy)benzoicacid (651 mg, 66%). ¹H NMR (400 MHz, DMSO-d6) δ 13.44 (s, 1H), 7.22 (d,J=2.8 Hz, 1H), 7.13 (d, J=8.8 Hz, 1H), 7.05 (dt, J=2.2, 1.0 Hz, 1H),6.99 (ddq, J=8.8, 2.4, 1.2 Hz, 1H), 6.43 (dt, J=2.2, 0.9 Hz, 1H), 3.80(s, 3H), 2.36 (s, 3H) ppm.

Step 2:2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-4-(trifluoromethoxy)benzamide

2-[2-Methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-4-(trifluoromethoxy)benzoicacid (200 mg, 0.469 mmol) was dissolved in dichloromethane (3 mL) andthe solution cooled in an ice bath under nitrogen atmosphere. Oxalylchloride (120 μL, 1.38 mmol) was added dropwise with stirring, followedby the addition of DMF (3 μL, 0.04 mmol). After stirring for 35 minutes,the reaction mixture was concentrated. The residue was redissolved indichloromethane (3 mL), cooled to 0° C. under nitrogen, and treated withammonia in dioxane (10 mL of 0.5 M, 5 mmol). After 5 minutes the icebath was removed and the resulting cloudy solution stirred for 30minutes. The reaction mixture was concentrated under reduced pressureand the residue partitioned between ethyl acetate and water. The aqueousphase was extracted with ethyl acetate and the combined organics washedwith brine, dried over Na₂SO₄, filtered and concentrated under reducedpressure to provide2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-4-(trifluoromethoxy)benzamide(184 mg, 83%). ESI-MS m/z calc. 425.07, found 426.0 (M+1)⁺; 424.0(M−1)⁻; Retention time (Method D): 0.94 minutes. ¹H NMR (400 MHz,DMSO-d6) δ 7.84 (s, 1H), 7.61 (s, 1H), 7.21 (d, J=2.7 Hz, 1H), 7.16 (d,J=8.8 Hz, 1H), 7.04-6.97 (m, 2H), 6.39-6.35 (m, 1H), 3.81 (s, 3H), 2.34(d, J=0.7 Hz, 3H) ppm.

Step 3:5-[[2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-4-(trifluoromethoxy)benzoyl]amino]pyridine-2-carboxamide(245)

2-[2-Methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-4-(trifluoromethoxy)benzamide(185 mg, 0.370 mmol), methyl 5-bromopyridine-2-carboxylate (96 mg, 0.44mmol), Xantphos (43 mg, 0.0743 mmol) and Cs₂CO₃ (266 mg, 0.816 mmol)were combined in dioxane (4 mL) under nitrogen. The mixture was degassed(2×vacuum-nitrogen cycles) and Pd(OAc)₂ (14 mg, 0.062 mmol) added. Themixture was again degassed (2×cycles) then heated at 100° C. for 60minutes. The reaction mixture was cooled to RT and partitioned betweenethyl acetate and water. The aqueous phase was extracted with additionalethyl acetate and the combined organics washed with brine, dried Na₂SO₄,filtered and concentrated under reduced pressure. The residue waspurified via silica gel chromatography (0-100% ethyl acetate/heptane) toprovide methyl5-(2-(2-methoxy-4-(trifluoromethoxy)phenoxy)-6-methyl-4-(trifluoromethoxy)benzamido)picolinate.The ester product was stirred with ammonia in methanol (5 mL of 7 M)under nitrogen overnight. The reaction mixture was concentrated andpurified by HPLC to provide5-[[2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-4-(trifluoromethoxy)benzoyl]amino]pyridine-2-carboxamide(98.5 mg, 48%). ESI-MS m/z calc. 545.10, found 546.0 (M+1)⁺; 544.0(M−1)⁻; Retention time (Method E): 3.35 minutes. ¹H NMR (500 MHz,DMSO-d6) δ 11.04 (s, 1H), 8.88 (dd, J=2.5, 0.7 Hz, 1H), 8.30 (dd, J=8.6,2.5 Hz, 1H), 8.08-8.01 (m, 1H), 7.99 (s, 1H), 7.53 (s, 1H), 7.25 (d,J=8.8 Hz, 1H), 7.19 (d, J=2.8 Hz, 1H), 7.13 (dd, J=2.2, 1.2 Hz, 1H),7.00 (ddd, J=8.9, 2.7, 1.3 Hz, 1H), 6.49 (d, J=2.0 Hz, 1H), 3.77 (s,3H), 2.39 (s, 3H) ppm.

Example 58N-(2-carbamoyl-4-pyridyl)-6-cyclopropyl-3-[2-methoxy-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-2-carboxamide(246)

Step 1:3-[2-Methoxy-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-2-carboxylicacid

To 3-fluoro-5-(trifluoromethyl)pyridine-2-carboxylic acid (1.40 g, 6.70mmol) in DMF (14 mL) was added 2-methoxy-4-(trifluoromethoxy)phenol(1.39 g, 6.69 mmol) and Cs₂CO₃ (6.54 g, 20.1 mmol). The reaction wasstirred at 90° C. for 72 hours. The reaction was filtered through a padof Celite and the filtrate was partitioned between water and ethylacetate. The organic layer was washed with water, aqueous NaHCO₃ andbrine, dried over Na₂SO₄, filtered and concentrated under reducedpressure. Silica gel chromatography (10-100% ethyl acetate/hexanes)provided3-[2-methoxy-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-2-carboxylicacid (1.80 g, 68%) as a white solid. ESI-MS m/z calc. 397.04, found398.2 (M+1)⁺; retention time (Method A): 0.61 minutes.

Step 2: methyl3-[2-methoxy-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-2-carboxylate

To an ice-cooled solution of3-[2-methoxy-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-2-carboxylicacid (4 g, 10.07 mmol) in dichloromethane (50 mL) was added DMF (50 μL,0.65 mmol) and carefully oxalyl chloride (2.7 mL, 31 mmol). The reactionmixture was allowed to warm to room temperature over 30 minutes.Methanol (15 mL, 370 mmol) was cautiously added and the resultingmixture was stirred at room temperature for 2 hours. The reactionmixture was concentrated under reduced pressure. The residue wasdissolved in ethyl acetate and washed with water (3×30 mL), dried overMgSO₄ and concentrated under reduced pressure to provide methyl3-[2-methoxy-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-2-carboxylate(3.8 g, 92%). ESI-MS m/z calc. 411.05, found 412.5 (M+1)⁺; Retentiontime (Method D): 0.96 minutes. ¹H NMR (500 MHz, Chloroform-d) δ 8.60 (d,J=1.6 Hz, 1H), 7.23 (dd, J=1.7, 0.7 Hz, 1H), 7.17-7.12 (m, 1H),6.92-6.85 (m, 2H), 4.00 (s, 3H), 3.77 (s, 3H) ppm.

Step 3: methyl3-[2-methoxy-4-(trifluoromethoxy)phenoxy]-1-oxido-5-(trifluoromethyl)pyridin-1-ium-2-carboxylate

To a solution of methyl3-[2-methoxy-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-2-carboxylate(1.9 g, 4.6 mmol) in dichloromethane (30 mL) at 0° C. was added ureahydrogen peroxide (915 mg, 9.73 mmol) followed by the slow addition oftrifluoroacetic anhydride (1.3 mL, 9.4 mmol). The resulting mixture wasstirred at room temperature for 2 hours, then diluted withdichloromethane (30 mL) and treated with a saturated aqueous solution ofNaHCO₃ (50 mL). The mixture was stirred for 40 minutes at roomtemperature. Additional dichloromethane (100 mL) was added and layerswere separated. The organic phase was washed with saturated aqueousNaHCO₃ (50 mL), 10% aqueous Na₂S₂O₃ (50 mL) and brine (50 mL), thendried over MgSO₄, filtered and concentrated under reduced pressure toafford methyl3-[2-methoxy-4-(trifluoromethoxy)phenoxy]-1-oxido-5-(trifluoromethyl)pyridin-1-ium-2-carboxylate(1.95 g, 99%). ESI-MS m/z calc. 427.05, found 428.5 (M+1)⁺; 426.6(M−1)⁻; Retention time (Method D): 0.88 minutes. ¹H NMR (500 MHz,Chloroform-d) δ 8.21 (dd, J=1.3, 0.7 Hz, 1H), 7.19 (dd, J=8.2, 0.8 Hz,1H), 6.93-6.86 (m, 2H), 6.68 (dd, J=1.4, 0.7 Hz, 1H), 4.03 (s, 3H), 3.81(s, 3H) ppm.

Step 4: methyl6-chloro-3-[2-methoxy-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-2-carboxylate

Methyl3-[2-methoxy-4-(trifluoromethoxy)phenoxy]-1-oxido-5-(trifluoromethyl)pyridin-1-ium-2-carboxylate(1.0 g, 2.3 mmol) in phosphoryl trichloride (10 mL, 107 mmol) wasstirred at 50° C. overnight. The reaction mixture was cooled to roomtemperature and concentrated under reduced pressure. The residue waspartitioned between ethyl acetate (80 mL) and saturated aqueous NaHCO₃(50 mL) and the layers separated. The organic layer was washed withbrine (50 mL), dried over MgSO₄, filtered and evaporated under reducedpressure to provide methyl6-chloro-3-[2-methoxy-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-2-carboxylate(874 mg, 84%). ESI-MS m/z calc. 445.02, found 446.4 (M+1)⁺; Retentiontime (Method D): 1.08 minutes. ¹H NMR (500 MHz, Chloroform-d) δ 7.35 (s,1H), 7.18-7.12 (m, 1H), 6.92-6.82 (m, 2H), 3.99 (s, 3H), 3.79 (s, 3H)ppm.

Step 5: methyl6-cyclopropyl-3-[2-methoxy-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-2-carboxylate

A mixture of methyl6-chloro-3-[2-methoxy-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-2-carboxylate(690 mg, 1.55 mmol), cyclopropyl boronic acid (1.20 g, 14.0 mmol), K₃PO₄(1.50 g, 7.07 mmol), Pd(OAc)₂ (175 mg, 0.780 mmol) andtricyclohexylphosphane (240 μL, 0.780 mmol) in toluene (14 mL) and water(3.5 mL) was heated at 100° C. for 1 hour. The reaction mixture wascooled to room temperature and filtered through Celite. HPLCpurification provided methyl6-cyclopropyl-3-[2-methoxy-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-2-carboxylate(522 mg, 75%). ¹H NMR (500 MHz, Chloroform-d) δ 7.28 (s, 1H), 7.04 (d,J=8.7 Hz, 1H), 6.88 (d, J=2.6 Hz, 1H), 6.85 (ddd, J=8.7, 2.7, 1.1 Hz,1H), 3.94 (s, 3H), 3.83 (s, 3H), 2.36-2.23 (m, 1H), 1.28-1.20 (m, 2H),1.11-1.01 (m, 2H) ppm.

Step 6:6-cyclopropyl-3-[2-methoxy-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-2-carboxylicacid

Sodium hydroxide (in water) (12 mL of 2 M, 24.00 mmol) was added to asolution of methyl6-cyclopropyl-3-[2-methoxy-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-2-carboxylate(600 mg, 1.329 mmol) in tetrahydrofuran (30 mL) at 0° C. and theresulting mixture stirred at RT for 2 h. The solvent was removed invacuo and the residual aqueous mixture was acidified to pH-2 by carefuladdition of 1N HCl. The resulting mixture was extracted with ethylacetate (3×30 mL) and the combined organic extracts were dried overMgSO₄ and concentrated under reduced pressure to leave6-cyclopropyl-3-[2-methoxy-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-2-carboxylicacid (560 mg, 96%). ¹H NMR (500 MHz, Chloroform-d) δ 10.53 (s, 1H), 7.24(s, 1H), 7.15-6.98 (m, 1H), 6.87-6.64 (m, 2H), 3.71 (s, 3H), 2.27 (tdd,J=7.9, 6.4, 3.2 Hz, 1H), 1.11 (d, J=6.3 Hz, 4H) ppm.

Step 7: methyl4-[[6-cyclopropyl-3-[2-methoxy-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-2-carbonyl]amino]pyridine-2-carboxylate

To an ice cold solution of methyl 4-aminopyridine-2-carboxylate (47 mg,0.1043 mmol) in DCM (2.8 mL) was added oxalyl chloride (20 uL, 0.229mmol) and DMF (0.5 uL, 0.0065 mmol) and the mixture was stirred at RTfor 30 minutes. The mixture was concentrated under reduced pressure andthe residue was dissolved in DCM (2.8 mL) and methyl4-aminopyridine-2-carboxylate (19 mg, 0.125 mmol) and DIEA (29 uL, 0.167mmol) were added and the mixture was stirred at RT for 30 minutes. Themixture was concentrated under reduced pressure and the residue waspurified by silica gel chromatography (EtOAc—heptane gradient) to givemethyl4-[[6-cyclopropyl-3-[2-methoxy-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-2-carbonyl]amino]pyridine-2-carboxylate(50 mg, 84%). ESI-MS m z calc. 571.1178, found 572.5 (M+1)⁺; Retentiontime (Method F): 1.06 minutes.

Step 8:N-(2-carbamoyl-4-pyridyl)-6-cyclopropyl-3-[2-methoxy-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-2-carboxamide(246)

Methyl4-[[6-cyclopropyl-3-[2-methoxy-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-2-carbonyl]amino]pyridine-2-carboxylate(50 mg, 0.088 mmol) was dissolved in a solution of ammonia in methanol(2.5 mL of 7 M, 17.5 mmol) and stirred at room temperature overnight.The reaction was evaporated under reduced pressure and purified viasilica gel chromatography (methanol/dichloromethane gradient).Additional purification via HPLC (CH₃CN gradient with ammonia modifier)providedN-(2-carbamoyl-4-pyridyl)-6-cyclopropyl-3-[2-methoxy-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-2-carboxamide(45 mg, 92%). ESI-MS m/z calc. 556.12, found 557.5 (M+1)⁺; 555.5 (M−1)⁻;Retention time (Method E): 3.54 minutes. ¹H NMR (500 MHz, DMSO-d6) δ11.01 (s, 1H), 8.54 (d, J=5.4 Hz, 1H), 8.32 (d, J=2.2 Hz, 1H), 8.09 (d,J=2.8 Hz, 1H), 7.88 (dd, J=5.5, 2.2 Hz, 1H), 7.64 (d, J=2.8 Hz, 1H),7.54 (s, 1H), 7.23-7.17 (m, 2H), 6.96 (ddt, J=8.9, 2.5, 1.2 Hz, 1H),3.78 (s, 3H), 3.18 (d, J=5.2 Hz, 1H), 1.22 (dt, J=6.1, 3.0 Hz, 2H), 1.12(dt, J=8.1, 3.3 Hz, 2H) ppm.

Example 59N-(2-carbamoyl-4-pyridyl)-3-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-5-(trifluoromethyl)pyridine-2-carboxamide(247)

Step 1:3-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-5-(trifluoromethyl)pyridine-2-carboxylicacid

Methyl6-chloro-3-[2-methoxy-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-2-carboxylate(295 mg, 0.662 mmol), Pd(dppf)Cl₂ (56 mg, 0.069 mmol), Cs₂CO₃ (646 mg,1.98 mmol) and potassium methyltrifluoroborate (81 mg, 0.67 mmol) in THF(10 mL) and water (1 mL) was heated to 80° C. and stirred for 68 hours.The reaction mixture was partitioned between ethyl acetate and water.The organic layer containing the ester product was concentrated and thecrude product purified via silica gel chromatography (0-20% ethylacetate/heptane gradient) to provide methyl3-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-5-(trifluoromethyl)pyridine-2-carboxylate(97 mg, 34%). ¹H NMR (500 MHz, DMSO-d6) δ 7.52 (s, 1H), 7.28-7.17 (m,2H), 6.98 (ddt, J=8.8, 2.4, 1.1 Hz, 1H), 3.84 (s, 3H), 3.79 (s, 3H),2.62 (q, J=1.7 Hz, 3H) ppm. The aqueous layer was acidified to pH3 with2 M HCl and extracted with ethyl acetate. The organic layer was driedover MgSO₄, filtered and concentrated under reduced pressure to provide3-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-5-(trifluoromethyl)pyridine-2-carboxylicacid (200 mg). ESI-MS m/z calc. 411.05, found 412.5 (M+1)⁺; 410.6(M−1)⁻; Retention time (Method D): 0.59 minutes.

Step 2:3-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-5-(trifluoromethyl)pyridine-2-carboxylicacid

To a solution of methyl3-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-5-(trifluoromethyl)pyridine-2-carboxylate(97 mg, 0.23 mmol) in THF (2 mL) was added NaOH (2 mL of 2 M, 4 mmol)and the reaction mixture was stirred at room temperature for 1 hour. Thereaction mixture was diluted with water and acidified to pH-3 with 2 MHCl. The aqueous layer was extracted with ethyl acetate. The organiclayer was dried over MgSO₄, filtered and concentrated under reducedpressure to provide3-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-5-(trifluoromethyl)pyridine-2-carboxylicacid (116 mg, 100%). ESI-MS m/z calc. 411.05, found 412.5 (M+1)⁺; 410.7(M−1)⁻; Retention time (Method D): 0.59 minutes. ¹H NMR (500 MHz,DMSO-d6) δ 7.45 (s, 1H), 7.23 (d, J=2.8 Hz, 1H), 7.17 (d, J=8.8 Hz, 1H),6.98 (ddd, J=8.8, 2.8, 1.3 Hz, 1H), 3.80 (s, 3H), 2.62 (d, J=1.8 Hz, 3H)ppm.

Step 3: methyl4-[[3-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-5-(trifluoromethyl)pyridine-2-carbonyl]amino]pyridine-2-carboxylate

To a solution of3-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-5-(trifluoromethyl)pyridine-2-carboxylicacid (109 mg, 0.239 mmol) in dichloromethane (1.5 mL) and DMF (2 μL,0.02 mmol) at 0° C. was added oxalyl chloride (6 mL, 69 mmol) and thereaction mixture was warmed to room temperature for 2 hours. Thereaction mixture was concentrate under reduced pressure. The residue wasdissolved in dichloromethane (1 mL) and added to a solution of methyl4-aminopyridine-2-carboxylate (33.6 mg, 0.2208 mmol) and Et₃N (100 μL,0.718 mmol) in dichloromethane (1 mL) at 0° C. The reaction was allowedto warm to RT and stirred for 1 hour. The reaction mixture partitionedbetween dichloromethane and water and the layers separated. The aqueouslayer was extracted with additional dichloromethane, and the combinedorganic extracts were dried over Na₂SO₄, filtered and concentrated underreduced pressure. Silica gel chromatography (0-60% ethyl acetate/heptanegradient) provided methyl4-[[3-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-5-(trifluoromethyl)pyridine-2-carbonyl]amino]pyridine-2-carboxylate(37 mg, 28%). ESI-MS m/z calc. 545.10, found 546.5 (M+1)⁺; 544.7 (M−1)⁻;Retention time (Method D): 0.97 minutes. ¹H NMR (500 MHz, DMSO-d6) δ11.25 (s, 1H), 8.62 (d, J=5.5 Hz, 1H), 8.44 (d, J=2.1 Hz, 1H), 7.90 (dd,J=5.5, 2.1 Hz, 1H), 7.58 (s, 1H), 7.29-7.14 (m, 2H), 6.96 (ddt, J=8.8,2.5, 1.3 Hz, 1H), 3.89 (s, 3H), 3.76 (s, 3H), 2.69 (q, J=1.6 Hz, 3H)ppm.

Step 4:N-(2-carbamoyl-4-pyridyl)-3-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-5-(trifluoromethyl)pyridine-2-carboxamide(247)

A solution of methyl4-[[3-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-5-(trifluoromethyl)pyridine-2-carbonyl]amino]pyridine-2-carboxylate(35 mg, 0.064 mmol) and ammonia in methanol (1 mL of 7 M, 7 mmol) wasstirred at RT for 20 hours. The reaction mixture was concentrated underreduced pressure. The residue was dissolved in dichloromethane (20 mL)and washed with water (3×15 mL). The organic layer was dried andconcentrated under reduced pressure. Silica gel chromatography (ethylacetate/heptane gradient) providedN-(2-carbamoyl-4-pyridyl)-3-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-5-(trifluoromethyl)pyridine-2-carboxamide(13 mg, 36%). ESI-MS m/z calc. 530.10, found 531.6 (M+1)⁺; 529.7 (M−1)⁻;Retention time (Method E): 3.34 minutes. ¹H NMR (500 MHz, DMSO-d6) δ11.20 (s, 1H), 8.54 (d, J=5.4 Hz, 1H), 8.38 (d, J=2.3 Hz, 1H), 8.08 (d,J=2.8 Hz, 1H), 7.89 (dd, J=5.4, 2.2 Hz, 1H), 7.63 (d, J=2.8 Hz, 1H),7.57 (s, 1H), 7.23 (d, J=8.8 Hz, 1H), 7.19 (d, J=2.8 Hz, 1H), 6.96 (ddt,J=8.7, 2.3, 1.2 Hz, 1H), 3.77 (s, 3H), 2.69 (q, J=1.7 Hz, 3H) ppm.

Example 604-[[4-cyclopropyl-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-benzoyl]amino]pyridine-2-carboxamide(248)

Step 1:4-bromo-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-benzonitrile

2-methoxy-4-(trifluoromethoxy)phenol (575.2 mg, 2.764 mmol),4-bromo-2-fluoro-6-methyl-benzonitrile (500 mg, 2.336 mmol) and Cs₂CO₃(908.8 mg, 2.789 mmol) in DMF (2.5 mL) were degassed with an N₂ purgeand heated at 90° C. in a sealed tube for 24 hours. The mixture wasallowed to cool and was diluted with EtOAc and washed with 2M NaOH (2×)and brine (2×). The organic layer was, dried (MgSO₄) and concentrated togive4-bromo-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-benzonitrile(910.5 mg, 97%). ¹H NMR (500 MHz, DMSO-d6) δ 7.44 (dd, J=1.7, 0.8 Hz,1H), 7.39 (d, J=8.8 Hz, 1H), 7.28 (d, J=2.7 Hz, 1H), 7.05 (ddq, J=8.8,2.5, 1.2 Hz, 1H), 6.73-6.65 (m, 1H), 3.81 (s, 3H) ppm. This was used inthe next step without further purification.

Step 2:4-cyclopropyl-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-benzonitrile

4-bromo-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-benzonitrile(469 mg, 1.166 mmol) in toluene (10 mL) and water (2.5 mL) was degassedwith N₂/vacuum cycles before the addition of cyclopropylboronic acid(305 mg, 3.551 mmol), palladium acetate (20.3 mg, 0.09042 mmol), K₃PO₄(502.2 mg, 2.366 mmol) and tricyclohexylphosphine (49.8 mg, 0.1776mmol). The mixture was heated at 100° C. under nitrogen for 1.5 hours.The mixture was allowed to cool and diluted with water (20 mL) and EtOAc(20 mL) and the layers were separated. The organic layer was dried(MgSO₄) and concentrated under reduced pressure. The material waspurified by chromatography on silica gel with an EtOAc/heptane gradientto give4-cyclopropyl-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-benzonitrile(284 mg, 67%). ESI-MS m/z calc. 363.10822, found 364.5 (M+1)⁺; Retentiontime (Method F): 1.07 minutes.

Step 3:4-cyclopropyl-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-benzamide

4-cyclopropyl-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-benzonitrile(284 mg, 0.782 mmol) in EtOH (3 mL) and NaOH (5.8 mL of 2 M, 11.60 mmol)was stirred at reflux for 3 hours. Additional solid NaOH (300 mg, 7.501mmol) was carefully added and the mixture was returned to reflux for 3hours. The mixture was allowed to cool and then diluted with EtOAc andwashed with brine. The organic layer was dried (MgSO₄) and concentratedto give4-cyclopropyl-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-benzamide.ESI-MS m/z calc. 381.1188, found 382.6 (M+1)⁺; Retention time (MethodF): 0.89 minutes. The material was taken directly into the next step.

Step 4:4-[[4-cyclopropyl-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-benzoyl]amino]pyridine-2-carboxamide(248)

Methyl 4-bromopyridine-2-carboxylate (208.3 mg, 0.964 mmol), Xantphos(96.6 mg, 0.167 mmol), cesium carbonate (613 mg, 1.881 mmol), Pd(OAc)₂(18.2 mg, 0.0811 mmol) and4-cyclopropyl-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-benzamide(298 mg, 0.782 mmol) were combined in dioxane (10 mL) and heated at 100°C. overnight. The mixture was allowed to cool and then diluted withEtOAc and washed with sat. aq. NaHCO₃. The organic layer was separated,dried (MgSO₄) and concentrate. Purification by silica gel chromatographyusing an EtOAc/heptane gradient gave the major product, which wastreated with NH₃ (in methanol) (6 mL of 7 M, 42.00 mmol) at RT for 3days. The mixture was concentrated and purified directly by HPLC to give4-[[4-cyclopropyl-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-benzoyl]amino]pyridine-2-carboxamide(26.5 mg, 7%). ¹H NMR (500 MHz, DMSO-d6) δ 10.93 (s, 1H), 8.49 (d, J=5.5Hz, 1H), 8.33 (d, J=2.1 Hz, 1H), 8.05 (d, J=2.9 Hz, 1H), 7.81 (dd,J=5.5, 2.2 Hz, 1H), 7.60 (d, J=2.9 Hz, 1H), 7.15-7.04 (m, 2H), 7.03-6.88(m, 1H), 6.73 (d, J=1.4 Hz, 1H), 6.37 (d, J=1.4 Hz, 1H), 3.75 (s, 3H),2.28 (s, 3H), 1.87 (tt, J=8.4, 5.0 Hz, 1H), 0.98-0.85 (m, 2H), 0.74-0.53(m, 2H) ppm. ESI-MS m/z calc. 501.15115, found 502.6 (M+1)⁺; Retentiontime (Method E): 3.31 minutes.

Example 614-[[2-fluoro-6-[2-hydroxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]-1-oxido-pyridin-1-ium-2-carboxamide(249)

Step 1:4-[[2-fluoro-6-[2-hydroxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide

To a stirred mixture of4-[[2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(200 mg, 0.375 mmol) in dichloromethane (2 mL) was added BBr₃ indichloromethane (approximately 1.509 mL of 1 M, 1.509 mmol) dropwise at−78° C. The reaction mixture was stirred at −78° C. for 5 min thenallowed to warm to RT and stirred overnight. The mixture was dilutedwith isopropyl acetate, washed with 50% of sat.d NaHCO₃, brine, driedover Na₂SO₄, and concentrated under reduced pressure. Purification bysilica gel chromatography eluting with an EtOAc/Hexane gradient, andtriturated with IPAc/heptane gave4-[[2-fluoro-6-[2-hydroxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide64 mg, 33%) as white solid. ¹H NMR (400 MHz, DMSO-d6) δ 11.42 (s, 1H),10.62 (s, 1H), 8.56 (d, J=5.4 Hz, 1H), 8.33 (d, J=2.1 Hz, 1H), 8.10 (d,J=2.9 Hz, 1H), 7.86 (dd, J=5.5, 2.2 Hz, 1H), 7.82 (t, J=8.6 Hz, 1H),7.66 (d, J=2.8 Hz, 1H), 7.31 (d, J=8.8 Hz, 1H), 6.99-6.92 (m, 1H),6.91-6.85 (m, 1H), 6.67 (d, J=8.9 Hz, 1H) ppm. ESI-MS m/z calc.519.0665, found 520.1 (M+1)⁺; Retention time (Method B): 1.67 minutes.

Step 2:4-[[2-fluoro-6-[2-hydroxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]-1-oxido-pyridin-1-ium-2-carboxamide(249)

To a stirring slurry of4-[[2-fluoro-6-[2-hydroxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(208 mg, 0.401 mmol) in anhydrous DCM (2 mL) under N₂ at 0° C. was added3-chlorobenzenecarboperoxoic acid (304.4 mg, 1.358 mmol). Then, thereaction was allowed to warm to RT and stirred for 23 h. The solvent wasevaporated under reduced pressure. The crude material was purified bysilica gel chromatography eluting with an ethyl acetate in hexanesgradient. The product was impure. It was re-purified by SFC to yield4-[[2-fluoro-6-[2-hydroxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]-1-oxido-pyridin-1-ium-2-carboxamide(103.6 mg, 48%) as a white solid. ¹H NMR (400 MHz, DMSO-d6) δ 11.58 (s,1H), 10.63 (s, 1H), 10.60 (d, J=4.5 Hz, 1H), 8.56 (d, J=3.2 Hz, 1H),8.38 (d, J=7.2 Hz, 1H), 8.28 (d, J=4.5 Hz, 1H), 7.88 (dd, J=7.2, 3.2 Hz,1H), 7.83 (t, J=8.6 Hz, 1H), 7.31 (d, J=8.8 Hz, 1H), 6.96 (d, J=2.8 Hz,1H), 6.93-6.83 (m, 1H), 6.68 (d, J=8.9 Hz, 1H) ppm. ESI-MS m/z calc.535.06146, found 536.13 (M+1)⁺; Retention time (Method C): 2.24 minutes.

Example 624-[[2-fluoro-6-[4-(trifluoromethoxy)phenyl]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(250)

Step 1:4-[[2-fluoro-6-[4-(trifluoromethoxy)phenyl]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(250)

A microwave vial was loaded with4-[[6-bromo-2-fluoro-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(100 mg, 0.246 mmol), [4-(trifluoromethoxy)phenyl]boronic acid (51 mg,0.248 mmol), potassium carbonate (68 mg, 0.4920 mmol), Pd(PPh₃)₄ (28 mg,0.0242 mmol), water (50 μL), and DMF (500 μL). The reaction mixture wasdegassed under nitrogen and stirred at 150° C. for 2 hours. The reactionwas diluted with DMSO (500 μL), filtered, and purified by reverse phasepreparative chromatography using a C18 column and a gradient eluent ofacetonitrile in water (5 mM HCl) to obtain4-[[2-fluoro-6-[4-(trifluoromethoxy)phenyl]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(11.4 mg, 9%). ESI-MS m/z calc. 487.0767, found 488.5 (M+1)⁺; Retentiontime (Method C): 2.41 minutes. ¹H NMR (400 MHz, DMSO-d6) δ 11.40 (s,1H), 8.51 (d, J=5.5 Hz, 1H), 8.17 (d, J=2.1 Hz, 1H), 8.11 (s, 1H), 8.04(t, J=7.9 Hz, 1H), 7.71-7.64 (m, 2H), 7.64-7.58 (m, 3H), 7.45 (d, J=8.2Hz, 2H) ppm.

The compounds set forth in Table 31 were prepared by methods analogousto the preparation of compound 250.

TABLE 31 Additional Compounds Prepared by Methods Analogous to Example62. Cmpd No. Compound Name LC/MS NMR (shifts in ppm) 2514-[[2-fluoro-6-(4-fluoro-2- ESI-MS m/z ¹H NMR (400 MHz, DMSO-d₆) δ 11.34methoxy-phenyl)-3- calc. 451.09552, (s, 1H), 8.52 (d, J = 5.6 Hz, 1H),8.24 (trifluoromethyl)benzoyl]ami- found 452.2 (d, J = 2.2 Hz, 1H), 8.17(s, 1H), 7.99 no]pyridine-2-carboxamide (M + 1)+; (t, J = 7.8 Hz, 1H),7.78-7.68 (m, 2H), Retention time 7.45 (d, J = 8.1 Hz, 1H), 7.33 (dd, J= 8.5, (Method B): 6.7 Hz, 1H), 7.00-6.94 (m, 1H), 6.91- 1.53 minutes6.83 (m, 1H), 3.60 (s, 3H).

Example 634-[[2-(4-fluoro-2-methoxy-phenyl)-5-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(252)

Step 1: methyl 2-bromo-5-(trifluoromethyl)benzoate

To a suspension of 2-bromo-5-(trifluoromethyl)benzoic acid (5.0 g, 18.59mmol), N,N-dimethylformamide (144 μL, 1.860 mmol), and DCM (50 mL),under nitrogen and at RT, was added oxalyl chloride (1.6 mL, 18.34mmol), in a single portion. The reaction was stirred at RT for 2 hours.The reaction mixture was concentrated to dryness under reduced pressure.To the residue was added DCM (50 mL) followed by methanol (7.5 mL, 185.1mmol) and the solution was stirred at RT for 1 hour. The reactionmixture was evaporated to dryness under reduced pressure and the residuewas purified by silica gel column chromatography using a gradient eluentof EtOAc in hexanes to give methyl 2-bromo-5-(trifluoromethyl)benzoate(4.3 g, 82%) as a clear oil. ¹H NMR (400 MHz, DMSO-d6) δ 8.11 (d, J=2.4Hz, 1H), 8.02 (dd, J=8.6, 1.1 Hz, 1H), 7.95-7.74 (m, 1H), 3.91 (s, 3H)ppm.

Step 2: methyl 2-(4-fluoro-2-methoxy-phenyl)-5-(trifluoromethyl)benzoate

A mixture of methyl 2-bromo-5-(trifluoromethyl)benzoate (500 mg, 1.77mmol), (4-fluoro-2-methoxy-phenyl)boronic acid (450 mg, 2.648 mmol),K₂CO₃ (488 mg, 3.531 mmol), Pd(PPh₃)₄ (41 mg, 0.0355 mmol), DMF (4.5mL), and water (500 μL) was stirred under nitrogen at 80° C. for 2hours. The solution was evaporated to dryness under reduced pressure andthe residue was purified by silica gel column chromatography using agradient eluent of EtOAc in hexanes to give methyl2-(4-fluoro-2-methoxy-phenyl)-5-(trifluoromethyl)benzoate (510 mg, 88%)as a clear oil. ¹H NMR (400 MHz, DMSO-d6) δ 8.02 (d, J=2.1 Hz, 1H),8.01-7.95 (m, 1H), 7.57 (d, J=8.0 Hz, 1H), 7.32 (dd, J=8.4, 6.8 Hz, 1H),6.98 (dd, J=11.3, 2.5 Hz, 1H), 6.89 (td, J=8.5, 2.5 Hz, 1H), 3.68 (s,3H), 3.66 (s, 3H) ppm.

Step 3: 2-(4-fluoro-2-methoxy-phenyl)-5-(trifluoromethyl)benzoic acid

A mixture of methyl2-(4-fluoro-2-methoxy-phenyl)-5-(trifluoromethyl)benzoate (500 mg, 1.523mmol), NaOH (609 mg, 15.23 mmol), H₂O (2.5 mL), and THF (2.5 mL) wasloaded into a sealed vessel and heated at 100° C. for 2 hours. Thereaction mixture was acidified to pH=2 (1.0 N aqueous HCl) andpartitioned between water (50 mL) and EtOAc (100 mL). The organic phasewas evaporated to dryness under reduced pressure and the residue waspurified by silica gel column chromatography using a gradient of EtOAcin hexanes to give2-(4-fluoro-2-methoxy-phenyl)-5-(trifluoromethyl)benzoic acid (340 mg,71%) as a white solid. ¹H NMR (400 MHz, DMSO-d6) δ 12.97 (s, 1H), 8.02(d, J=2.1 Hz, 1H), 7.93 (dd, J=8.2, 2.1 Hz, 1H), 7.53 (d, J=8.0 Hz, 1H),7.27 (dd, J=8.4, 6.8 Hz, 1H), 6.97 (dd, J=11.4, 2.5 Hz, 1H), 6.86 (td,J=8.4, 2.4 Hz, 1H), 3.69 (s, 3H) ppm.

Step 4:4-[[2-(4-fluoro-2-methoxy-phenyl)-5-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(252)

To a stirring solution of2-(4-fluoro-2-methoxy-phenyl)-5-(trifluoromethyl)benzoic acid (150 mg,0.477 mmol), DMF (4 μL, 0.0517 mmol), and dichloromethane (2 mL), at 0°C. (ice-bath), was added oxalyl chloride (83 μL, 0.925 mmol) dropwiseover 3 minutes. The mixture was stirred at RT for 2 hours and thesolvent was evaporated under reduced pressure to afford the acidchloride intermediate. This intermediate was dissolved in DCM (5 mL) andadded dropwise to a 0° C. (ice-bath) solution of4-aminopyridine-2-carboxamide (66 mg, 0.481 mmol), DIEA (208 μL, 1.194mmol), and dichloromethane (1 mL). The reaction mixture was stirred atRT for 2 hours. The reaction mixture was concentrated under reducedpressure and the residue was purified by silica gel columnchromatography using a gradient of MeOH in dichloromethane to give anorange semisolid. This material was triturated with diethyl ether (100mL) and filtered to give4-[[2-(4-fluoro-2-methoxy-phenyl)-5-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(16 mg, 8%) as a white solid. ESI-MS m/z calc. 433.10495, found 434.0(M+1)⁺; Retention time (Method B): 1.5 minutes. ¹H NMR (400 MHz,DMSO-d6) δ 11.05 (s, 1H), 8.51 (d, J=5.7 Hz, 1H), 8.31 (d, J=2.2 Hz,1H), 8.20 (s, 1H), 8.02 (d, J=2.0 Hz, 1H), 7.97 (dd, J=8.1, 2.0 Hz, 1H),7.82 (dd, J=5.7, 2.1 Hz, 1H), 7.74 (s, 1H), 7.62 (d, J=8.1 Hz, 1H), 7.37(dd, J=8.3, 6.8 Hz, 1H), 7.00-6.75 (m, 2H), 3.54 (s, 3H) ppm.

The compounds set forth in Table 32 were prepared by methods analogousto the preparation of compound 252.

TABLE 32 Additional Compounds Prepared by Methods Analogous to Example63. Cmpd No. Compound Name LC/MS NMR (shifts in ppm) 253N-(3-carbamoyl-4-fluoro- ESI-MS m/z 1H NMR (400 MHz, DMSO-d6) δphenyl)-2-(4-fluoro-2- calc. 450.10028, 10.45 (s, 1H), 7.97-7.87 (m,3H), 7.75- methoxy-phenyl)-5- found 451.0 7.62 (m, 3H), 7.59 (d, J = 7.9Hz, 1H), (trifluoromethyl)benzamide (M + 1)+; 7.33 (dd, J = 8.4, 6.8 Hz,1H), 7.23 Retention time (dd, J = 10.2, 8.9 Hz, 1H), 6.92 (dd, (MethodB): J = 11.3, 2.4 Hz, 1H), 6.86 (td, J = 1.56 minutes 8.4, 2.4 Hz, 1H),3.59 (s, 3H).

Example 644-[[2-[4-(trifluoromethoxy)phenyl]-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(254)

Step 1:4-[[2-[4-(trifluoromethoxy)phenyl]-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(254)

A microwave vial was loaded with4-[[2-bromo-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide (100mg, 0.2576 mmol), [4-(trifluoromethoxy)phenyl]boronic acid (53 mg,0.2574 mmol), potassium carbonate (71 mg, 0.5137 mmol), Pd(PPh₃)₄ (30mg, 0.0260 mmol), water (50 μL), and DMF (500 μL). The reaction mixturewas degassed under nitrogen and stirred at 150° C. for 2 hours. Thereaction was diluted with DMSO (500 μL), filtered, and purified byreverse phase preparative chromatography using a C18 column and agradient eluent of acetonitrile in water (5 mM HCl) to obtain4-[[2-[4-(trifluoromethoxy)phenyl]-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(2.0 mg, 2%). ESI-MS m/z calc. 469.08612, found 470.3 (M+1)⁺; Retentiontime (Method B): 1.72 minutes. ¹H NMR (400 MHz, DMSO-d₆) δ 11.10 (s,1H), 8.49 (d, J=5.5 Hz, 1H), 8.21 (s, 1H), 8.13 (s, 1H), 8.00-7.91 (m,2H), 7.88 (s, 1H), 7.75-7.64 (m, 2H), 7.64-7.53 (m, 2H), 7.43 (s, 1H),7.41 (s, 1H) ppm.

Example 654-[[2-bromo-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(255)

Step 1:4-[[2-bromo-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(255)

4-[[2-Bromo-6-fluoro-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(1.00 g, 2.462 mmol), 2-methoxy-4-(trifluoromethoxy)phenol (564 mg,2.710 mmol) and Cs₂CO₃ (1.60 g, 4.911 mmol) were combined in NMP (15 mL)and heated at 95° C. for 2 hours. The reaction mixture was partitionedbetween ethyl acetate and water. The organic layer was separated andwashed with water and brine. The organic layer was dried over MgSO₄,filtered and concentrated. Silica gel chromatography (ethylacetate/dichloromethane gradient) provided4-[[2-bromo-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(690 mg, 47%). ESI-MS m/z calc. 593.0021, found 595.0 (M+1)⁺; Retentiontime (Method B): 1.68 minutes. ¹H NMR (400 MHz, DMSO-d6) δ 11.14 (s,1H), 8.44 (d, J=5.5 Hz, 1H), 8.05 (dd, J=13.5, 2.5 Hz, 2H), 7.93-7.81(m, 2H), 7.63 (d, J=2.8 Hz, 1H), 7.48 (dd, J=5.6, 2.2 Hz, 1H), 6.86 (d,J=2.5 Hz, 1H), 6.79 (d, J=8.8 Hz, 1H), 6.73 (d, J=8.6 Hz, 1H), 3.50 (s,3H) ppm.

Example 665-[[5-chloro-2-[[5-(trifluoromethoxy)-2-pyridyl]oxy]benzoyl]amino]-2-fluoro-benzamide(256)

Step 1: methyl 5-chloro-2-[[5-(trifluoromethoxy)-2-pyridyl]oxy]benzoate

A microwave vial was loaded with methyl 5-chloro-2-hydroxy-benzoate (100mg, 0.536 mmol), 2-bromo-5-(trifluoromethoxy)pyridine (155 mg, 0.6405mmol), iodocopper (10 mg, 0.05251 mmol), K₃PO₄ (353 mg, 1.071 mmol), andpyridine-2-carboxylic acid (13 mg, 0.1056 mmol). The vial was capped,flushed with nitrogen and anhydrous DMSO (500 μL) was added via syringe.The reaction mixture was heated at 80° C. for 19 hours. The reaction wasdiluted with DMSO (500 μL), filtered, and purified by reverse phasepreparative chromatography using a C18 column and a gradient ofacetonitrile in water (5 mM HCl) to give methyl5-chloro-2-[[5-(trifluoromethoxy)-2-pyridyl]oxy]benzoate (58 mg, 31%) asa clear oil. ESI-MS m/z calc. 347.0172, found 347.9 (M+1)⁺; Retentiontime (Method B): 1.92 minutes. ¹H NMR (400 MHz, DMSO-d6) δ 8.17 (d,J=2.9 Hz, 1H), 8.03-7.95 (m, 1H), 7.90 (d, J=2.7 Hz, 1H), 7.76 (dd,J=8.7, 2.7 Hz, 1H), 7.39 (d, J=8.7 Hz, 1H), 7.25 (d, J=9.0 Hz, 1H), 3.61(s, 3H) ppm.

Step 2: 5-chloro-2-[[5-(trifluoromethoxy)-2-pyridyl]oxy]benzoic acid

A mixture of methyl5-chloro-2-[[5-(trifluoromethoxy)-2-pyridyl]oxy]benzoate (50 mg, 0.141mmol), NaOH (113 mg, 2.825 mmol), H₂O (500 μL), and THF (500 μL) wasloaded into a microwave vessel and heated at 100° C. for 2 hours. Thereaction mixture was acidified to pH=2 (1.0 N aqueous HCl) andpartitioned between water (50 mL) and EtOAc (100 mL). The organicportion was evaporated to dryness under reduced pressure and the residuewas purified by silica gel column chromatography using a gradient ofEtOAc in hexanes to give5-chloro-2-[[5-(trifluoromethoxy)-2-pyridyl]oxy]benzoic acid (32 mg,67%) as a white solid. ESI-MS m/z calc. 333.00156, found 333.8 (M+1)⁺;Retention time (Method B): 1.61 minutes. ¹H NMR (400 MHz, DMSO-d6) δ13.17 (s, 1H), 8.17 (d, J=2.9 Hz, 1H), 7.96 (dd, J=9.0, 2.9 Hz, 1H),7.88 (d, J=2.7 Hz, 1H), 7.72 (dd, J=8.7, 2.7 Hz, 1H), 7.34 (d, J=8.7 Hz,1H), 7.22 (d, J=9.0 Hz, 1H) ppm.

Step 3:5-[[5-chloro-2-[[5-(trifluoromethoxy)-2-pyridyl]oxy]benzoyl]amino]-2-fluoro-benzamide(256)

To a stirring solution of5-chloro-2-[[5-(trifluoromethoxy)-2-pyridyl]oxy]benzoic acid (50 mg,0.147 mmol), N,N-dimethylformamide (0.6 μL, 0.00775 mmol), and DCM (500μL) was added oxalyl chloride (130 μL, 1.490 mmol) portion wise over 3minutes. The mixture was stirred at RT for 2 hours and the solvent wasevaporated under reduced pressure to afford the acid chlorideintermediate. The intermediate was dissolved in DCM (200 μL) and addeddropwise to a 0° C. (ice-bath) solution of 5-amino-2-fluoro-benzamide(34 mg, 0.221 mmol), Et₃N (52 μL, 0.373 mmol), HATU (56 mg, 0.147 mmol),and DCM (500 μL). The reaction mixture was stirred at RT for 2 hours.The reaction mixture was concentrated under reduced pressure and theresidue was purified by silica gel column chromatography using agradient of MeOH in dichloromethane to give an orange semisolid. Thismaterial was triturated with diethyl ether (100 mL) and filtered to give5-[[5-chloro-2-[[5-(trifluoromethoxy)-2-pyridyl]oxy]benzoyl]amino]-2-fluoro-benzamide(38 mg, 53%) as a white solid. ESI-MS m/z calc. 469.04526, found 469.9(M+1)⁺; Retention time (Method B): 1.57 minutes. ¹H NMR (400 MHz,DMSO-d6) δ 10.54 (s, 1H), 8.18 (d, J=3.0 Hz, 1H), 7.92 (dd, J=9.0, 2.9Hz, 1H), 7.88 (dd, J=6.5, 2.7 Hz, 1H), 7.76 (d, J=2.7 Hz, 1H), 7.64(dtt, J=7.3, 4.5, 2.7 Hz, 4H), 7.38 (d, J=8.7 Hz, 1H), 7.25-7.12 (m, 2H)ppm.

Example 674-[[3-cyclobutyl-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzoyl]amino]pyridine-2-carboxamide(257)

Step 1: methyl3-cyclobutyl-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzoate

To a vial charged with methyl3-bromo-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzoate (75mg, 0.172 mmol), palladium tritert-butylphosphane (4 mg, 0.00783 mmol),and THF (0.5 mL) under an atmosphere of N₂ at 0° C. was addedbromo(cyclobutyl)zinc (448 μL of 0.5 M, 0.2240 mmol) in THF slowly andthe reaction mixture was gradually warmed to RT over 1 h. Stirring wascontinued at RT for 30 minutes. The reaction mixture was quenched with1N HCl, and the aq. layer was extracted with DCM (3×). The combinedorganic layers were dried over Na₂SO₄, filtered and concentrated underreduced pressure. The residue was purified by silica gel chromatographyusing a gradient of ethyl acetate in hexanes to yield methyl3-cyclobutyl-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzoate(65 mg, 87%). ¹H NMR (400 MHz, Chloroform-d) δ 7.15 (d, J=8.6 Hz, 1H),6.92 (d, J=8.8 Hz, 1H), 6.85-6.81 (m, 1H), 6.75 (ddt, J=8.7, 2.7, 1.1Hz, 1H), 6.58 (d, J=8.5 Hz, 1H), 3.85 (s, 3H), 3.83 (s, 3H), 3.59 (p,J=8.8 Hz, 1H), 2.41-2.28 (m, 2H), 2.20 (s, 3H), 2.15-1.95 (m, 3H),1.89-1.74 (m, 1H) ppm. ESI-MS m/z calc. 410.1341, found 411.28 (M+1)⁺;Retention time (Method A): 0.88 minutes.

Step 2:3-cyclobutyl-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzoicacid

To a solution of methyl3-cyclobutyl-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzoate(63 mg, 0.146 mmol) in DMSO (2 mL) was added lithium hydroxidemonohydrate (75 mg, 1.787 mmol) in water (1.5 mL) and mixture was heatedat 140° C. for 4 hours. After cooling to RT, 1 N HCl was added toacidify the mixture and it was extracted with DCM (3×). The combinedorganics were dried over Na₂SO₄, and concentrated under reduced pressureto give3-cyclobutyl-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzoicacid (52 mg, 83%). ESI-MS m/z calc. 396.11847, found 397.27 (M+1)⁺;Retention time (Method A): 0.84 minutes.

Step 3:4-[[3-cyclobutyl-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzoyl]amino]pyridine-2-carboxamide(257)

To a solution of3-cyclobutyl-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzoicacid (50 mg, 0.126 mmol) in DCM (1.5 mL) cooled in an ice bath was addedDMF (1.3 μL, 0.0168 mmol) followed by the drop wise addition of oxalylchloride (22 μL, 0.252 mmol). The mixture was stirred at on ice for 10minutes then at RT for 2 h. The reaction was concentrated under reducedpressure and flushed with N₂ to afford the acid chloride, which wastaken directly into the next step. A solution of methyl4-aminopyridine-2-carboxylate (19 mg, 0.1249 mmol) and DIEA (56 μL,0.321 mmol) in DCM (1.5 mL) was cool on ice and the crude acid chloridein DCM (1.5 mL) was added drop wise. The ice bath was removed and thereaction mixture was stirred at RT overnight. The reaction was quenchedinto water and extract with DCM (3×). The combined organics were driedover Na₂SO₄, filter and concentrated under reduced pressure. The majorproduct was isolated by silica gel column chromatography using agradient of ethyl acetate in hexanes which was used directly in the nextstep. The isolated material was treated with NH₃ (7 mL of 7 M, 49.00mmol) in methanol for 16 hours. The solvent was removed under reducedpressure to give4-[[3-cyclobutyl-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzoyl]amino]pyridine-2-carboxamide(31 mg, 48%). ¹H NMR (400 MHz, Chloroform-d) δ 8.71 (s, 1H), 8.49 (d,J=5.6 Hz, 1H), 8.36 (s, 1H), 7.87 (d, J=2.1 Hz, 2H), 7.18 (d, J=8.6 Hz,1H), 7.13-7.01 (m, 1H), 6.84 (d, J=7.6 Hz, 2H), 6.56 (d, J=8.6 Hz, 1H),5.48 (s, 1H), 3.85 (s, 3H), 3.62 (p, J=9.1 Hz, 1H), 2.34 (s, 4H),2.18-1.93 (m, 3H), 1.90-1.73 (m, 1H), 1.25 (s, 1H) ppm. ESI-MS m/z calc.515.1668, found 516.4 (M+1)⁺; Retention time (Method B): 1.87.

Example 684-[[2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-[4-(trifluoromethyl)cyclohexyl]benzoyl]amino]pyridine-2-carboxamide(two diastereoisomers) (158)

Step 1.4-[[2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-[4-(trifluoromethyl)cyclohexen-1-yl]benzoyl]amino]pyridine-2-carboxamide

A 4-mL vial charged with4-[[4-bromo-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(30 mg, 0.057 mmol),4,4,5,5-tetramethyl-2-[4-(trifluoromethyl)cyclohexen-1-yl]-1,3,2-dioxaborolane(31.5 mg, 0.114 mmol), K₂CO₃ (8 mg, 0.06 mmol), Pd(dppf)Cl₂.DCM (5 mg,0.006 mmol) in dioxane (500 μL) and water (50 μL) was flushed withnitrogen and heated at 100° C. for 16 hours. The reaction mixture wasfiltered and purified by HPLC (CH₃CN/5 mM HCl) to provide4-[[2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-[4-(trifluoromethyl)cyclohexen-1-yl]benzoyl]amino]pyridine-2-carboxamide(33 mg, 97%). ESI-MS m/z calc. 584.48, found 585.1 (M+1)⁺; Retentiontime (Method B): 1.94 minutes.

Step 2.4-[[2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-[4-(trifluoromethyl)cyclohexyl]benzoyl]amino]pyridine-2-carboxamide(two diastereoisomers) (158)

4-[[2-[2-Methoxy-4-(trifluoromethoxy)phenoxy]-4-[4-(trifluoromethyl)cyclohexen-1-yl]benzoyl]amino]pyridine-2-carboxamide(20 mg, 0.034 mmol) was dissolved in ethyl acetate (500 μL) and methanol(500 μL) and treated with 10% Pd/C (10 mg, 0.009 mmol). The mixture wasdegassed with a flow of nitrogen for 2 minutes, and then stirred at roomtemperature under hydrogen atmosphere (balloon) for 16 hours. Thereaction mixture was filtered and purified HPLC (1-99% CH₃CN/5 mM HCl)to provide the two diastereomers. It is appreciated that bothdiastereomers of4-[[2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-[4-(trifluoromethyl)cyclohexyl]benzoyl]amino]pyridine-2-carboxamide(158) were isolated and that those diastereomers have the structure ofcompounds 158-a and 158-b (above). However, the relative stereochemistryof the first and second eluting diastereomers was not determined.

Diastereomer 1:4-[[2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-[4-(trifluoromethyl)cyclohexyl]benzoyl]amino]pyridine-2-carboxamide(8.5 mg, 42%). ESI-MS m/z calc. 597.17, found 598.2 (M+1)⁺; Retentiontime (Method B): 2.02 minutes. ¹H NMR (400 MHz, DMSO-d₆) δ 10.85 (s,1H), 8.51 (d, J=5.6 Hz, 1H), 8.33 (d, J=2.2 Hz, 1H), 8.14 (s, 1H), 7.87(dd, J=5.6, 2.2 Hz, 1H), 7.71-7.60 (m, 2H), 7.22 (d, J=8.8 Hz, 1H),7.19-7.12 (m, 2H), 6.99 (d, J=8.8 Hz, 1H), 6.65 (d, J=1.5 Hz, 1H), 3.74(s, 3H), 2.78 (s, 1H), 2.48 (m, 1H, obscured by solvent peak), 1.70 (d,J=8.6 Hz, 8H) ppm.

Diastereomer 2:4-[[2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-[4-(trifluoromethyl)cyclohexyl]benzoyl]amino]pyridine-2-carboxamide(4.5 mg, 22%). ESI-MS m/z calc. 597.17, found 598.3 (M+1)⁺; Retentiontime (Method B): 2.08 minutes. ¹H NMR (400 MHz, DMSO-d₆) δ 10.90 (s,1H), 8.51 (d, J=5.6 Hz, 1H), 8.34 (d, J=2.1 Hz, 1H), 8.18 (s, 1H), 7.87(dd, J=5.7, 2.2 Hz, 1H), 7.72 (s, 1H), 7.62 (d, J=7.9 Hz, 1H), 7.28-7.06(m, 3H), 6.98 (d, J=8.8 Hz, 1H), 6.70 (s, 1H), 3.75 (s, 3H), 2.43-2.23(m, 1H), 2.02-1.73 (m, 4H), 1.58-1.28 (m, 4H) ppm.

Example 694-[[2,3-difluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(259)

Step 1: 2,3-difluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoicacid

6-Bromo-2,3-difluoro-benzoic acid (2.97 g, 12.5 mmol) and2-methoxy-4-(trifluoromethoxy)phenol (3.28 g, 15.8 mmol) were dissolvedin toluene (60 mL) and the solution was purged with nitrogen(3×vacuum/nitrogen backfill). Cs₂CO₃ (8.22 g, 25.2 mmol) was added andthe mixture was stirred for 5 minutes. Copper (I) iodide (486 mg, 2.55mmol) was added and the mixture again purged with nitrogen (3×). Themixture was stirred at 100° C. overnight. After cooling to roomtemperature, the mixture was acidified to pH 2 with 1 M aqueous HCl andpartitioned between ethyl acetate and water. The layers were separatedand the aqueous layer was extracted with additional ethyl acetate. Thecombined organic layers were washed with brine and aqueous Na₂S20₃,dried over MgSO₄ and concentrated in vacuo. Silica gel chromatography(0-5% methanol/dichloromethane) provided2,3-difluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoic acid (1.93g, 42%). ESI-MS m z calc. 364.04, found 363.3 (M−1)⁻; LC/MS retentiontime (Method F): 0.55 minutes. ¹H NMR (500 MHz, CDCl₃) δ 7.17 (td,J=9.3, 8.4 Hz, 1H), 7.13-7.09 (m, 1H), 6.85 (qt, J=2.7, 1.3 Hz, 2H),6.50 (ddd, J=9.3, 3.5, 2.0 Hz, 1H), 3.81 (s, 3H) ppm.

Step 2: methyl4-[[2,3-difluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxylate

A solution of2,3-difluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoic acid (306mg, 0.840 mmol) and DMF (5 μL, 0.07 mmol) in dichloromethane (7.5 mL) at0° C. was treated dropwise with oxalyl chloride (190 μL, 2.18 mmol). Themixture was allowed to warm to room temperature and stirred for 1 hour.The mixture was then concentrated in vacuo, redissolved indichloromethane (4.5 mL) and added dropwise to a solution of methyl4-aminopyridine-2-carboxylate (138 mg, 0.907 mmol) and TEA (300 μL, 2.15mmol) in dichloromethane (4.5 mL) at 0° C. The mixture was allowed tocome to room temperature and stirred overnight. The mixture waspartitioned between dichloromethane and water and filtered through aphase separator cartridge. The organic phase was concentrated in vacuo.Silica gel chromatography (0-100% ethyl acetate/heptane) provided methyl4-[[2,3-difluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxylate(134 mg, 32%). ESI-MS m z calc. 498.08502, found 499.5 (M+1)⁺; 497.4(M−1)⁻; LC/MS retention time (Method F): 0.91 minutes. ¹H NMR (500 MHz,CDCl₃) δ 8.98 (s, 1H), 8.68 (d, J=5.5 Hz, 1H), 8.13-8.09 (m, 1H), 8.03(d, J=2.1 Hz, 1H), 7.23-7.13 (m, 2H), 6.96-6.90 (m, 2H), 6.52 (ddd,J=9.3, 3.5, 1.9 Hz, 1H), 4.01 (s, 3H), 3.92 (s, 3H) ppm.

Step 3:4-[[2,3-difluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(259)

Methyl4-[[2,3-difluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxylate(134 mg, 0.269 mmol) was dissolved in a solution of ammonia in methanol(4 mL of 7 M, 28 mmol) and stirred at room temperature overnight. Themixture was concentrated in vacuo and treated with additional ammonia inmethanol (4 mL of 7 M, 28 mmol) and stirred at room temperature for 5hours. The mixture was concentrated in vacuo and purified by reversephase HPLC (38-53% acetonitrile/0.1% ammonium hydroxide) to provide4-[[2,3-difluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(70 mg, 54%) as an off white solid. ESI-MS m z calc. 483.09, found 484.5(M+1)⁺; 482.4 (M−1)⁻; LC/MS retention time (Method E): 3.01 minutes. ¹HNMR (500 MHz, CDCl₃) δ 8.97 (s, 1H), 8.53 (d, J=5.6 Hz, 1H), 8.39 (dd,J=5.6, 2.2 Hz, 1H), 7.85 (s, 1H), 7.79 (d, J=2.2 Hz, 1H), 7.21-7.14 (m,2H), 6.92 (d, J=8.1 Hz, 2H), 6.52 (dt, J=9.5, 2.8 Hz, 1H), 5.50 (s, 1H),3.92 (s, 3H) ppm.

Example 704-[[2,3-difluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]-5-methyl-pyridine-2-carboxamide(260)

Step 1: methyl4-[[2,3-difluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]-5-methyl-pyridine-2-carboxylate

A solution of2,3-difluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoic acid (293mg, 0.805 mmol) and DMF (5 μL, 0.07 mmol) in dichloromethane (6.5 mL) at0° C. was treated dropwise with oxalyl chloride (180 μL, 2.06 mmol). Themixture was allowed to warm to room temperature and stirred for 1 hour.The mixture was concentrated in vacuo, redissolved in dichloromethane (4mL) and added dropwise to a solution of methyl4-amino-5-methyl-pyridine-2-carboxylate (136 mg, 0.818 mmol,Preparation 1) and TEA (290 μL, 2.08 mmol) in dichloromethane (4 mL) at0° C. The solution was allowed to come to room temperature and stirredovernight. The mixture was partitioned between dichloromethane and waterand filtered through a phase separator cartridge. The organic phase wasconcentrated in vacuo. Silica gel chromatography (0-100% ethylacetate/heptane) provided methyl4-[[2,3-difluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]-5-methyl-pyridine-2-carboxylate(120 mg, 29%). ESI-MS m z calc. 512.10, found 511.4 (M−1)⁻; LC/MSretention time (Method F): 0.93 minutes. ¹H NMR (500 MHz, CDCl₃) δ 9.07(s, 1H), 8.51 (s, 2H), 7.17 (dd, J=8.7, 5.7 Hz, 2H), 6.95-6.88 (m, 2H),6.48-6.44 (m, 1H), 4.01 (s, 3H), 3.79 (s, 3H), 2.25 (s, 3H) ppm.

Step 2:4-[[2,3-difluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]-5-methyl-pyridine-2-carboxamide(260)

Methyl4-[[2,3-difluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]-5-methyl-pyridine-2-carboxylate(120 mg, 0.234 mmol) was dissolved in a solution of ammonia in methanol(3.5 mL of 7 M, 24.5 mmol) and stirred at room temperature overnight.The mixture was concentrated in vacuo and purified by reverse phase HPLC(38-53% acetonitrile/0.1% ammonium hydroxide) to provide4-[[2,3-difluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]-5-methyl-pyridine-2-carboxamide(78 mg, 65%) as an off-white solid. ESI-MS m z calc. 497.10, found 498.2(M+1)⁺; 496.4 (M−1)⁻; LC/MS retention time (Method E): 3.05 minutes. HNMR (500 MHz, CDCl₃) δ 8.98 (s, 1H), 8.43 (s, 1H), 8.34 (s, 1H), 7.84(s, 1H), 7.16 (dd, J=16.1, 8.6 Hz, 2H), 6.93-6.87 (m, 2H), 6.47-6.42 (m,1H), 5.54 (s, 1H), 3.79 (s, 3H), 2.26 (s, 3H) ppm.

Example 714-[[3-chloro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzoyl]amino]pyridine-2-carboxamide(261)

Step 1: 3-chloro-6-iodo-2-methyl-benzoic acid

3-Chloro-2-methyl-benzoic acid (4.9 g, 29 mmol), N-iodosuccinimide (9.2g, 41 mmol) and Pd(OAc)₂ (320 mg, 1.43 mmol) were added to a flask,which was evacuated/backfilled with nitrogen (3×). DMF (30 mL) was addedand the mixture was heated at 100° C. for 4 hours. The mixture wascooled, then diluted with ethyl acetate (250 mL) and washed with water(5×100 mL). The organic layer was dried over MgSO₄, filtered andconcentrated in vacuo to provide 3-chloro-6-iodo-2-methyl-benzoic acid(8.22 g, 97%). ESI-MS m z calc. 295.91, found 295.4 (M−1)⁻; LC/MSretention time (Method F): 0.34 minutes. ¹H NMR (500 MHz, DMSO-d₆) δ13.81 (s, 1H), 7.71 (d, J=8.4 Hz, 1H), 7.25 (d, J=8.4 Hz, 1H), 2.31 (s,3H) ppm.

Step 2:3-chloro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzoic acid

A solution of 3-chloro-6-iodo-2-methyl-benzoic acid (2.21 g, 7.45 mmol)in toluene (10 mL) was treated with copper (I) iodide (152 mg, 0.798mmol), Cs₂CO₃ (4.82 g, 14.8 mmol) and2-methoxy-4-(trifluoromethoxy)phenol (1.97 g, 9.47 mmol), then degassedvia vacuum/nitrogen backfill. The flask was sealed and heated at 100° C.for 5 hours. The mixture was diluted with ethyl acetate and washed withbrine (2×) and saturated aqueous NaHCO₃ (2×). The organic layer wasdried over MgSO₄, filtered and concentrated. The residue was purified bysilica gel chromatography (0-100% ethyl acetate/heptane) to provide3-chloro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzoic acid(2.26 g, 80%). ESI-MS m z calc. 376.03, found 375.5 (M−1)⁻; LC/MSretention time (Method F): 0.6 minutes.

Step 3:4-[[3-chloro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzoyl]amino]pyridine-2-carboxamide(261)

To a solution of3-chloro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzoic acid(100 mg, 0.266 mmol) and DMF (2 μL, 0.03 mmol) in dichloromethane (2 mL)at 0° C. was added oxalyl chloride (70 μL, 0.83 mmol) dropwise. Themixture was stirred for 1 hour, then concentrated in vacuo. The residuewas redissolved in dichloromethane (2 mL) and added dropwise to amixture of methyl 4-aminopyridine-2-carboxylate (50 mg, 0.33 mmol) andTEA (220 μL, 1.58 mmol) in dichloromethane (2 mL) at 0° C. The resultingmixture was stirred and warmed to room temperature overnight. Themixture was concentrated in vacuo and treated with a solution of ammoniain methanol (5 mL of 7 M, 35.00 mmol) and stirred at room temperatureovernight. The mixture was concentrated in vacuo and the residuepurified by reverse phase HPLC (47-95% acetonitrile/0.1% ammoniumhydroxide) to provide4-[[3-chloro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzoyl]amino]pyridine-2-carboxamide(1.4 mg, 1%) as an off-white solid. ESI-MS m z calc. 495.08, found 496.1(M+1)⁺; 494.2 (M−1)⁻; LC/MS retention time (Method F): 0.91 minutes. ¹HNMR (400 MHz, CDCl₃) δ 8.92 (s, 1H), 8.54 (d, J=5.6 Hz, 1H), 8.40 (d,J=5.5 Hz, 1H), 7.94 (d, J=2.1 Hz, 1H), 7.33 (d, J=8.9 Hz, 1H), 7.29-7.13(m, 1H), 6.93-6.84 (m, 2H), 6.56 (dd, J=9.0, 0.7 Hz, 1H), 5.47 (s, 1H),3.89 (s, 3H), 2.52 (s, 3H) ppm.

Example 725-[[2,3,4-trifluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyrimidine-2-carboxamide(262)

Step 1: 6-bromo-2,3,4-trifluoro-benzoic acid

Diisopropylamine (2.87 g, 3.98 mL, 28.4 mmol) was diluted in 2-MeTHF (40mL) and the solution was cooled to −20° C. A solution of n-butyllithium(10.4 mL of 2.5 M in hexanes, 26 mmol) was added over 15 minutes and themixture was stirred for 15 minutes at −20° C. The solution was cooled to−78° C. and treated with a solution of 5-bromo-1,2,3-trifluoro-benzene(4.97 g, 23.6 mmol) in 2-MeTHF (2 mL) over 15 minutes. The mixture wasstirred for 90 minutes, and then carbon dioxide (8 g, 182 mmol) pelletswere added in one portion at −78° C. After the carbon dioxide addition,an exotherm reaching −59° C. was observed and the mixture was cooledback to −78° C. The mixture was warmed to −20° C. over 15 minutes, thentreated with water (20 mL) and 3 M aqueous HCl (10 mL) over 5 minutesuntil the pH was about 1. The phases were separated and the aqueouslayer was extracted with MTBE (25 mL). Combined organic layers wereextracted with 2 M aqueous NaOH (2×25 mL). The combined aqueous layerswere acidified with concentrated aqueous HCl (12 M, 10 mL) to pH=1. Theaqueous layer was extracted with MTBE (2×25 mL). The organic layer waswashed with 1 M aqueous HCl (30 mL) and brine, dried over anhydrousNa₂SO₄, filtered and concentrated in vacuo to provide6-bromo-2,3,4-trifluoro-benzoic acid (4.8 g, 78%) as a white solid.ESI-MS m z calc. 253.92, found 253.0 (M−1)⁻; LC/MS retention time(Method O): 1.51 minutes. ¹H NMR (400 MHz, DMSO-d₆) δ 14.90-14.09 (m,1H), 7.94-7.84 (m, 1H) ppm. ¹⁹F NMR (377 MHz, DMSO-d₆) δ −131.44 (dd,J=21.8, 6.8 Hz, 1F), −134.62-−134.89 (m, 1F), −159.54-−159.74 (m, 1F)ppm.

Step 2: 2,3,4-trifluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoicacid

A mixture of 6-bromo-2,3,4-trifluoro-benzoic acid (544 mg, 2.13 mmol),Cs₂CO₃ (1.4 g, 4.3 mmol), copper (I) iodide (92 mg, 0.49 mmol) and2-methoxy-4-(trifluoromethoxy)phenol (675 mg, 3.24 mmol) in toluene (5.5mL) was flushed with nitrogen and stirred at 100° C. for 6 hours. Aftercooling to room temperature, water and ethyl acetate were added to themixture and the layers were separated. The aqueous layer was acidifiedwith concentrated HCl to ˜pH 1 and extracted with ethyl acetate (3×).The combined organic phases were dried over Na₂SO₄, filtered andconcentrated in vacuo. Silica gel chromatography (ethyl acetate/hexanegradient) provided2,3,4-trifluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoic acid(143.6 mg, 18%). ESI-MS m z calc. 382.03, found 383.1 (M+1)⁺; LC/MSretention time (Method B): 1.82 minutes.

Step 3:5-[[2,3,4-trifluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyrimidine-2-carboxamide(262)

To a solution of2,3,4-trifluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoic acid(162 mg, 0.424 mmol) and DMF (15 μL, 0.19 mmol) in dichloromethane (3.0mL) at 0° C. was added oxalyl chloride (105 μL, 1.20 mmol) dropwiseunder nitrogen atmosphere. The ice bath was removed after 10 minutes andthe mixture was stirred at room temperature for 1 hour. The mixture wasconcentrated in vacuo to afford2,3,4-trifluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoylchloride. The acid chloride was dissolved in NMP (1 mL), cooled to 0° C.and treated with a solution of methyl 5-aminopyrimidine-2-carboxylate(131 mg, 0.855 mmol) and DIEA (370 μL, 2.12 mmol) in NMP (1 mL). Themixture was stirred at room temperature for 1 hour, and then heated at75° C. for 1 hour. Purification by reverse phase HPLC (10-99%acetonitrile/5 mM HCl) provided methyl5-[[2,3,4-trifluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyrimidine-2-carboxylate(75.1 mg, 34%). The solid was treated with a solution of ammonia inmethanol (2 mL of 7 M, 14 mmol) and the mixture was stirred at 75° C.for 1.5 hours in a pressure vessel. The mixture was concentrated invacuo, filtered and purified by reverse phase HPLC (10-99%acetonitrile/5 mM HCl) to provide5-[[2,3,4-trifluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyrimidine-2-carboxamide(37.6 mg, 18%) as a white solid. ESI-MS m z calc. 502.07, found 503.0(M+1)⁺; LC/MS retention time (Method C): 2.17 minutes. ¹H NMR (400 MHz,DMSO-d₆) δ 11.50 (s, 1H), 9.15 (s, 2H), 8.13 (s, 1H), 7.74 (s, 1H), 7.26(d, J=8.8 Hz, 1H), 7.18 (d, J=2.8 Hz, 1H), 7.01-6.95 (m, 1H), 6.95-6.88(m, 1H), 3.76 (s, 3H) ppm.

Example 734-[[2,3-difluoro-4-methoxy-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(263)

Step 1: 6-bromo-2,3-difluoro-4-methoxy-benzoic acid

A solution of diisopropylamine (11.6 g, 16 mL, 114 mmol) in THF (160 mL)was cooled to −20° C. n-Butyllithium (42 mL of 2.3 M, 96.6 mmol) wasadded at such a rate to maintain the internal temperature below −15° C.The cooling bath was then removed and the mixture was allowed to warm to0° C. and stirred at room temperature for 15 minutes. The mixture wascooled to −78° C. and treated dropwise with a solution of5-bromo-1,2-difluoro-3-methoxy-benzene (20.0 g, 89.7 mmol) in THF (80mL) over 30 minutes. The mixture was stirred for an additional 30minutes at −78° C. Excess solid carbon dioxide was added to the mixture.The mixture was allowed to warm to room temperature and stirred for 30minutes. A solution of 2 M aqueous HCl (100 mL) was added and themixture extracted with ethyl acetate (500 mL). The organic phase wasdried over Na₂SO₄ and concentrated in vacuo. The residue was dissolvedin 2 M aqueous NaOH (100 mL) and washed with ethyl acetate (500 mL). Theaqueous phase was acidified with 2 M aqueous HCl and extracted withethyl acetate (2×300 mL). The organic layer was dried over Na₂SO₄,filtered and concentrated in vacuo to provide6-bromo-2,3-difluoro-4-methoxy-benzoic acid (13 g, 54%) as a whitesolid. ESI-MS m z calc. 265.94, found 264.8 (M−1)⁻; LC/MS retention time(Method P): 1.67 minutes. ¹H NMR (400 MHz, DMSO-d₆) δ 14.06 (s, 1H),7.39 (d, J=6.76 Hz, 1H), 3.93 (s, 3H) ppm.

Step 2:2,3-difluoro-4-methoxy-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoicacid

A mixture of 6-bromo-2,3-difluoro-4-methoxy-benzoic acid (1.5 g, 5.6mmol), 2-methoxy-4-(trifluoromethoxy)phenol (1.0 g, 4.8 mmol) and Cs₂CO₃(1.98 g, 6.08 mmol) in toluene (25 mL) was bubbled with nitrogen for 10minutes, then copper (I) iodide (375 mg, 1.97 mmol) was added and themixture heated at 100° C. with vigorous stirring for 30 minutes. Themixture was cooled to room temperature and acidified with aqueous HCl,filtered and the aqueous layer extracted with ethyl acetate (3×50 mL).The combined organic layers were washed with brine, dried over MgSO₄,filtered and concentrated. Silica chromatography (0-100% ethylacetate/hexanes) provided2,3-difluoro-4-methoxy-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoicacid (488 mg, 22%) as a pale yellow powder. ESI-MS m z calc. 394.05,found 395.5 (M+1)⁺; 393.6 (M−1)⁻; LC/MS retention time (Method F): 0.55minutes. ¹H NMR (500 MHz, DMSO-d₆) δ 13.48 (s, 1H), 7.18 (d, J=2.7 Hz,1H), 6.98 (d, J=8.8 Hz, 1H), 6.92 (ddd, J=8.8, 2.7, 1.2 Hz, 1H), 6.54(dd, J=6.6, 1.9 Hz, 1H), 3.83 (s, 3H), 3.79 (s, 3H) ppm.

Step 3: methyl4-[[2,3-difluoro-4-methoxy-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxylate

A solution of2,3-difluoro-4-methoxy-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoicacid (80 mg, 0.20 mmol) was dissolved in dichloromethane (2.7 mL),cooled to 0° C. and treated with oxalyl chloride (47 μL, 0.54 mmol)followed by addition of DMF (1.7 μL, 0.02 mmol). The resulting mixturewas stirred for 1 hour and concentrated in vacuo. The residue wasdissolved in dichloromethane (2.7 mL) and methyl4-aminopyridine-2-carboxylate (31 mg, 0.20 mmol) and triethylamine (63μL, 0.45 mmol) added. The resulting mixture was stirred at roomtemperature overnight, and then concentrated in vacuo and purified bysilica gel chromatography (0-100% ethyl acetate/heptane) to providemethyl4-[[2,3-difluoro-4-methoxy-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxylate(24 mg, 22%) as a white powder. ESI-MS m z calc. 528.10, found 529.5(M+1)⁺; 527.6 (M−1)⁻; LC/MS retention time (Method F): 0.89 minutes.

Step 4:4-[[2,3-difluoro-4-methoxy-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(263)

A solution of ammonia in methanol (1 mL of 7 M, 7 mmol) was added tomethyl4-[[2,3-difluoro-4-methoxy-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxylate(24 mg, 0.045 mmol) and the resulting mixture was stirred at roomtemperature for 3 hours. The mixture was concentrated in vacuo andpurified by reverse phase HPLC (38-53% acetonitrile/0.1% ammoniumhydroxide) to provide4-[[2,3-difluoro-4-methoxy-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(8.4 mg, 35%) as a white powder. ESI-MS m z calc. 513.10, found 514.5(M+1)⁺; 512.6 (M−1)⁻; LC/MS retention time (Method E): 3.03 minutes. HNMR (500 MHz, DMSO-d₆) δ 11.17 (s, 1H), 8.51 (d, J=5.5 Hz, 1H), 8.24 (d,J=2.1 Hz, 1H), 8.07 (d, J=2.9 Hz, 1H), 7.76 (dd, J=5.4, 2.2 Hz, 1H),7.63 (d, J=2.8 Hz, 1H), 7.15-7.08 (m, 2H), 6.92 (ddd, J=8.9, 2.8, 1.2Hz, 1H), 6.60 (dd, J=6.5, 1.8 Hz, 1H), 3.83 (s, 3H), 3.75 (s, 3H) ppm.

Example 744-[[4-cyclopropyl-3-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzoyl]amino]pyridine-2-carboxamide(264)

Step 1: 4-cyclopropyl-3-fluoro-2-methyl-benzoic acid

A mixture of 4-bromo-3-fluoro-2-methyl-benzoic acid (2.238 g, 9.604mmol), cyclopropylboronic acid (1.648 g, 19.19 mmol),tricyclohexylphosphine (270 mg, 0.963 mmol), K₃PO4 (7.144 g, 33.66 mmol)and Pd(OAc)₂ (110 mg, 0.490 mmol) in toluene (50 mL) and water (12.5 mL)was purged with nitrogen and stirred at 100° C. for 60 hours. Themixture was diluted with water (75 mL) and washed with ethyl acetate(3×75 mL). The aqueous layer was acidified to pH 3 and extracted withethyl acetate (3×100 mL). The combined organic extracts were dried andconcentrated in vacuo to provide 4-cyclopropyl-3-fluoro-2-methyl-benzoicacid (1.816 g, 97%). ESI-MS m z calc. 194.07, found 193.7 (M−1)⁻; LC/MSretention time (Method F): 0.35 minutes. ¹H NMR (500 MHz, DMSO-d₆) δ12.88 (s, 1H), 7.55 (dd, J=8.2, 1.1 Hz, 1H), 6.87 (t, J=7.9 Hz, 1H),2.43 (d, J=2.7 Hz, 3H), 2.08 (tt, J=8.5, 5.2 Hz, 1H), 1.10-0.92 (m, 2H),0.82-0.69 (m, 2H) ppm.

Step 2: 4-cyclopropyl-3-fluoro-6-iodo-2-methyl-benzoic acid

To a vial was added 4-cyclopropyl-3-fluoro-2-methyl-benzoic acid (1.0 g,5.2 mmol), N-iodosuccinimide (1.280 g, 5.689 mmol) and Pd(OAc)₂ (110 mg,0.490 mmol). The vial was evacuated and filled with nitrogen threetimes. DMF (40 mL) was added and the mixture was heated at 110° C. for30 minutes. The mixture was diluted with water (100 mL) and extractedwith ethyl acetate (100 mL). The organic layer was washed with water(3×100 mL), dried, filtered and concentrated in vacuo to provide4-cyclopropyl-3-fluoro-6-iodo-2-methyl-benzoic acid (1.442 g, 88%).ESI-MS m z calc. 319.97, found 319.3 (M−1)⁻; LC/MS retention time: 0.43minutes (Method F). ¹H NMR (500 MHz, DMSO-d₆) δ 13.61 (s, 1H), 7.25 (d,J=6.9 Hz, 1H), 2.19 (d, J=2.5 Hz, 3H), 2.04-1.93 (m, 1H), 1.04-0.90 (m,2H), 0.84-0.69 (m, 2H) ppm.

Step 3:4-cyclopropyl-3-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzoicacid

A vial containing 2-methoxy-4-(trifluoromethoxy)phenol (480 mg, 2.31mmol), copper (I) iodide (425 mg, 2.23 mmol) and Cs₂CO₃ (1.093 g, 3.355mmol) was evacuated and purged with nitrogen. A solution of4-cyclopropyl-3-fluoro-6-iodo-2-methyl-benzoic acid (715 mg, 2.23 mmol)in toluene (12.5 mL) was added and the mixture heated at 100° C. for 20hours. The mixture was diluted with water and extracted with ethylacetate (4×20 mL). The combined organic extracts were dried andconcentrated in vacuo. The residue was purified by silica gelchromatography (0-100% ethyl acetate/heptane) to provide4-cyclopropyl-3-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzoicacid (292 mg, 33%). ESI-MS m z calc. 400.09, found 399.5 (M−1)⁻; LC/MSretention time (Method F): 0.62 minutes. ¹H NMR (500 MHz, DMSO-d₆) δ13.29 (s, 1H), 7.13 (d, J=2.7 Hz, 1H), 6.88 (d, J=9.1 Hz, 1H), 6.79 (d,J=8.8 Hz, 1H), 6.32 (d, J=6.0 Hz, 1H), 3.82 (s, 3H), 2.21 (d, J=2.4 Hz,3H), 2.08-1.95 (m, 1H), 1.01-0.87 (m, 2H), 0.66-0.52 (m, 2H) ppm.

Step 4: methyl4-[[4-cyclopropyl-3-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzoyl]amino]pyridine-2-carboxylate

A solution of4-cyclopropyl-3-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzoicacid (140 mg, 0.35 mmol) and DMF (3 μL, 0.04 mmol) in dichloromethane (3mL) was treated with oxalyl chloride (90 μL, 1.0 mmol) at 0° C. Themixture was allowed to warm to room temperature and stirred for 30minutes. The mixture was then concentrated in vacuo. The residue wasdissolved in dichloromethane (2 mL) and added to a solution of methyl4-aminopyridine-2-carboxylate (64.1 mg, 0.421 mmol) and TEA (150 μL,1.076 mmol) in dichloromethane (2 mL) at 0° C. The mixture was warmed toroom temperature and stirred for 2 hours. The mixture was diluted withdichloromethane (30 mL) and washed with water (25 mL). The aqueous layerwas extracted with additional dichloromethane (3×20 mL), and thecombined organic extracts dried and concentrated in vacuo. The residuewas purified by silica gel chromatography (0-70% ethyl acetate/heptane)to provide methyl4-[[4-cyclopropyl-3-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzoyl]amino]pyridine-2-carboxylate(68 mg, 36%). ESI-MS m z calc. 534.14, found 535.6 (M+1)⁺; 533.6 (M−1)⁻;LC/MS retention time (Method F): 0.95 minutes.

Step 5:4-[[4-cyclopropyl-3-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzoyl]amino]pyridine-2-carboxamide(264)

Methyl4-[[4-cyclopropyl-3-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzoyl]amino]pyridine-2-carboxylate(67 mg, 0.13 mmol) was dissolved in a solution of ammonia in methanol (2mL of 7 M, 14 mmol) and stirred at room temperature for 20 hours. Themixture was concentrated in vacuo and purified by reverse phase HPLC(47-95% acetonitrile/0.1% ammonium hydroxide) to provide4-[[4-cyclopropyl-3-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzoyl]amino]pyridine-2-carboxamide(33 mg, 50%). ESI-MS m z calc. 519.14, found 520.6 (M+1)⁺; 518.7 (M−1)⁻;LC/MS retention time (Method E): 3.39 minutes. ¹H NMR (500 MHz, DMSO-d₆)δ 11.00 (s, 1H), 8.48 (d, J=5.5 Hz, 1H), 8.27 (d, J=2.1 Hz, 1H), 8.05(d, J=2.9 Hz, 1H), 7.76 (dd, J=5.5, 2.2 Hz, 1H), 7.60 (d, J=2.9 Hz, 1H),7.06 (d, J=2.7 Hz, 1H), 6.97 (d, J=8.8 Hz, 1H), 6.92-6.86 (m, 1H), 6.34(d, J=5.9 Hz, 1H), 3.70 (s, 3H), 2.22 (d, J=2.3 Hz, 3H), 2.05 (ddd,J=13.5, 8.6, 5.1 Hz, 1H), 1.02-0.91 (m, 2H), 0.69-0.56 (m, 2H) ppm.

Example 754-[[3-chloro-4-methoxy-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzoyl]amino]pyridine-2-carboxamide(265)

Step 1: (4-bromo-2-chloro-phenoxy)-tert-butyl-dimethyl-silane

To a solution of 4-bromo-2-chloro-phenol (1.0 g, 4.8 mmol) in DMF (4 mL)was added imidazole (660 mg, 9.70 mmol) and TBSCl (727 mg, 4.82 mmol)and the mixture was stirred at room temperature for 4 hours. AdditionalTBSCl (727 mg, 4.82 mmol) and imidazole (660 mg, 9.70 mmol) were addedand the mixture was stirred for 12 hours. The mixture was diluted withethyl acetate (100 mL) and washed with saturated aqueous NH₄Cl (2×200mL), water (3×200 mL) and brine, dried over Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by silica gelchromatography (100% hexanes) to provide(4-bromo-2-chloro-phenoxy)-tert-butyl-dimethyl-silane (1.35 g, 86%) as acolorless oil. ¹H NMR (250 MHz, CDCl₃) δ 7.48 (d, J=2.5 Hz, 1H), 7.22(dd, J=8.6, 2.4 Hz, 1H), 6.75 (d, J=8.6 Hz, 1H), 1.02 (s, 9H), 0.22 (s,6H) ppm.

Step 2: (4-bromo-2-chloro-3-methyl-phenoxy)-tert-butyl-dimethyl-silane

To a solution of diisopropylamine (10.3 g, 14.2 mL, 101 mmol, freshlydistilled from CaH₂) in THF (222 mL) at 0° C. was added n-butyllithium(40 mL of 2.5 M in hexanes, 100 mmol). The solution was stirred for 20minutes at this temperature, then cooled to −78° C. and stirred for 15minutes. A solution of(4-bromo-2-chloro-phenoxy)-tert-butyl-dimethyl-silane (30.0 g, 92.3mmol) in THF (66 mL) was transferred to the LDA solution dropwise viacannula and the mixture stirred at −78° C. for 4 hours. Methyl iodide(22.8 g, 10 mL, 160 mmol) was then added dropwise. The mixture wasstirred for 30 minutes at −78° C. then the cooling bath was removed andstirred for 30 minutes at room temperature. The mixture was diluted withsaturated aqueous NH₄Cl (150 mL) and extracted with ethyl acetate (3×500mL). The combined organic layers were washed with 0.1 M aqueous HCl,saturated aqueous NaHCO₃, and brine, dried over Na₂SO₄, filtered andconcentrated in vacuo to provide(4-bromo-2-chloro-3-methyl-phenoxy)-tert-butyl-dimethyl-silane (34 g,77%) as a colorless oil. ¹H NMR (250 MHz, CDCl₃) δ 7.30 (d, J=8.7 Hz,1H), 6.63 (d, J=8.7 Hz, 1H), 2.50 (s, 3H), 1.02 (s, 9H), 0.21 (s, 6H)ppm.

Step 3: 1-bromo-3-chloro-4-methoxy-2-methyl-benzene

To a flask containing neat(4-bromo-2-chloro-3-methyl-phenoxy)-tert-butyl-dimethyl-silane (29.99 g,89.33 mmol) was added methyl iodide (25.1 g, 11.0 mL, 177 mmol). Themixture was stirred for 5 minutes then treated with a solution of TBAFin THF (160 mL of 1 M, 160 mmol). The mixture was stirred for 12 hoursat room temperature, then diluted with 0.5 M aqueous HCl (200 mL) andextracted with MTBE (3×750 mL). The combined organic extracts werewashed with water (3×700 mL) and brine, dried over MgSO₄, filtered andconcentrated in vacuo. The residue was purified by silica gelchromatography (0-5% diethyl ether/hexanes) to provide1-bromo-3-chloro-4-methoxy-2-methyl-benzene (15.85 g, 65%) as acolorless oil. ¹H NMR (500 MHz, CDCl₃) δ 7.41 (d, J=8.9 Hz, 1H), 6.68(d, J=8.9 Hz, 1H), 3.88 (s, 3H), 2.52 (s, 3H) ppm.

Step 4: 3-chloro-4-methoxy-2-methyl-benzoic acid

A solution of 1-bromo-3-chloro-4-methoxy-2-methyl-benzene (310 mg, 1.30mmol) in THF (10 mL) was stirred at −78° C. for 15 minutes undernitrogen, then n-butyllithium (0.54 mL of 2.5 M, 1.35 mmol) was addedand the mixture stirred at this temperature for 9 minutes. Thesuspension was transferred via cannula onto solid crushed carbon dioxide(dry ice) and the mixture allowed to warm to room temperature. Theresulting solution was diluted with 0.5 M aqueous HCl (until pH=3) andextracted with ethyl acetate (3×50 mL). The combined organic extractswere dried over MgSO₄, filtered and concentrated in vacuo to provide3-chloro-4-methoxy-2-methyl-benzoic acid (180 mg, 68%) as a white solid.ESI-MS m z calc. 200.02, found 201.3 (M+1)⁺; LC/MS retention time(Method Q): 1.85 minutes. ¹H NMR (500 MHz, CDCl₃) δ 8.01 (d, J=8.9 Hz,1H), 6.85 (d, J=8.8 Hz, 1H), 3.97 (s, 3H), 2.74 (s, 3H), 1.65 (br s, 1H)ppm.

Step 5: 3-chloro-6-iodo-4-methoxy-2-methyl-benzoic acid

A solution of 3-chloro-4-methoxy-2-methyl-benzoic acid (4.25 g, 21.2mmol), N-iodosuccinimide (5.24 g, 23.3 mmol) and Pd(OAc)₂ (1.19 g, 5.30mmol) in DMF (24 mL) was heated at 65° C. for 22 hours under nitrogen.Additional N-iodosuccinimide (1.19 g, 5.29 mmol) and Pd(OAc)₂ (238 mg,1.06 mmol) were added at room temperature and the mixture heated at 55°C. for an additional 12 hours. The mixture was cooled to 0° C., dilutedwith 1 M aqueous HCl (150 mL) and extracted with ethyl acetate (3×100mL). The combined organics were extracted with 1 M aqueous NaOH (2×100mL) and the combined aqueous extracts washed with hexanes (3×100 mL).The aqueous phase was acidified with 3 M aqueous HCl at 0° C. andextracted with ethyl acetate (50 mL). The combined organic extracts werewashed with aqueous sodium metabisulfite (10%, 2×40 mL), 0.1 M HCl(2×200 mL) and brine, dried over Na₂SO₄, filtered and concentrated invacuo to provide 3-chloro-6-iodo-4-methoxy-2-methyl-benzoic acid (4.81g, 61%) as a white solid. ESI-MS m z calc. 325.92, found 327.3 (M+1)⁺;LC/MS retention time (Method N): 4.46 minutes. ¹H NMR (500 MHz, DMSO-d₆)δ 13.55 (s, 1H), 7.41 (s, 1H), 3.87 (s, 3H), 2.30 (s, 3H) ppm.

Step 6:3-chloro-4-methoxy-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzoicacid

To a solution of 3-chloro-6-iodo-4-methoxy-2-methyl-benzoic acid (2.0 g,6.1 mmol) in DMF (6 mL) was added Cs₂CO₃ (6.0 g, 18.4 mmol),2-methoxy-4-(trifluoromethoxy)phenol (1.91 g, 9.18 mmol), copper (I)iodide (58 mg, 0.31 mmol) and pyridine (1.0 mL, 12.4 mmol). The mixturewas heated at 80° C. under nitrogen for 4 hours. The mixture was cooledto room temperature, treated with additional2-methoxy-4-(trifluoromethoxy)phenol (1.79 g, 8.60 mmol) and copper (29mg, 0.46 mmol), and then heated at 100° C. for 1 hour. The mixture wascooled to 0° C., acidified with 1 M aqueous HCl (until pH=2) andextracted with ethyl acetate (200 mL). The organic layer was washed with0.1 M aqueous HCl (3×75 mL) and brine, dried over Na₂SO₄, filtered andconcentrated in vacuo. The resulting residue was brought up indichloromethane and filtered. The filtrate was concentrated in vacuo andpurified by silica gel chromatography (0-20% ethyl acetate/hexanescontaining 1.5% acetic acid) to provide3-chloro-4-methoxy-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzoicacid (640 mg, 25%) as a crystalline solid. ESI-MS m z calc. 406.04,found 407.2 (M+1)⁺; LC/MS retention time (Method Q): 2.61 minutes. ¹HNMR (500 MHz, DMSO-d₆) δ 13.21 (s, 1H), 7.17 (d, J=2.5 Hz, 1H),6.98-6.83 (m, 2H), 6.46 (s, 1H), 3.83 (s, 3H), 3.72 (s, 3H), 2.33 (s,3H) ppm.

Step 7: methyl4-[[3-chloro-4-methoxy-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzoyl]amino]pyridine-2-carboxylate

A solution of3-chloro-4-methoxy-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzoicacid (135 mg, 0.331 mmol) and DMF (0.6 μL, 0.008 mmol) indichloromethane (2.5 mL) was cooled to 0° C. and treated with oxalylchloride (105 μL, 1.204 mmol). The mixture was stirred for 1 hour, thenconcentrated in vacuo. The residue was dissolved in a minimum amount ofdichloromethane and added to a suspension of methyl4-aminopyridine-2-carboxylate (68 mg, 0.44 mmol) in minimaldichloromethane and TEA (66 μL, 0.47 mmol) at 0° C. The reaction flaskwas removed from the ice bath after 10 minutes and the mixture stirredat room temperature overnight. The mixture was heated at 40° C. for 1hour, then cooled to room temperature and diluted with dichloromethane.The organic solution was washed with brine (2×), dried over MgSO₄,filtered and concentrated in vacuo. Purification by silica gelchromatography (0-30% ethyl acetate/heptane) provided methyl4-[[3-chloro-4-methoxy-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzoyl]amino]pyridine-2-carboxylate(59.9 mg, 33%). ESI-MS m z calc. 540.09, found 541.7 (M+1)⁺; LC/MSretention time (Method F): 0.94 minutes.

Step 8:4-[[3-chloro-4-methoxy-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzoyl]amino]pyridine-2-carboxamide(265)

Methyl4-[[3-chloro-4-methoxy-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzoyl]amino]pyridine-2-carboxylate(59.9 mg, 0.111 mmol) was dissolved in a solution of ammonia in methanol(6.5 mL of 7 M, 45.5 mmol) and stirred at room temperature for 1 hour.Additional ammonia solution (5 mL of 7 M, 35.00 mmol) was added and themixture stirred for 16 hours. The solution was partially concentratedunder vacuum, and then diluted with ethyl acetate and then washed with 2M aqueous NaOH and water. The organic layer was concentrated in vacuoand purified by reverse phase HPLC (38-53% acetonitrile/0.1% ammoniumhydroxide) to provide4-[[3-chloro-4-methoxy-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-benzoyl]amino]pyridine-2-carboxamide(37.9 mg, 63%). ESI-MS m z calc. 525.09, found 526.6 (M+1)⁺; LC/MSretention time (Method E): 3.16 minutes. ¹H NMR (500 MHz, DMSO-d₆) δ11.00 (s, 1H), 8.50 (d, J=5.5 Hz, 1H), 8.29 (d, J=2.2 Hz, 1H), 8.06 (d,J=2.8 Hz, 1H), 7.79 (dd, J=5.5, 2.2 Hz, 1H), 7.61 (d, J=2.9 Hz, 1H),7.11 (dd, J=5.8, 3.0 Hz, 2H), 6.93 (ddd, J=8.8, 2.8, 1.3 Hz, 1H), 6.49(s, 1H), 3.75 (s, 3H), 3.74 (s, 3H), 2.34 (s, 3H) ppm.

Example 764-[[3-chloro-2-fluoro-4-methoxy-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(266)

Step 1: 5-bromo-2-chloro-1-fluoro-3-methoxy-benzene

To a solution of 5-bromo-2-chloro-1,3-difluoro-benzene (1.033 g, 4.542mmol) in DMF (15 mL) at 0° C. was added sodium methoxide (10 mL of 0.5 Min methanol, 5 mmol). The mixture was warmed to room temperature andstirred for 16 hours. The mixture was diluted with water (200 mL) andextracted with ethyl acetate (200 mL). The organic layer was washed withwater (3×200 mL), dried over MgSO₄, filtered and concentrated in vacuoto provide 5-bromo-2-chloro-1-fluoro-3-methoxy-benzene (1.021 g, 94%).¹H NMR (500 MHz, CDCl₃) δ 6.98 (dd, J=8.0, 2.0 Hz, 1H), 6.87 (t, J=1.9Hz, 1H), 3.91 (s, 3H) ppm.

Step 2: 6-bromo-3-chloro-2-fluoro-4-methoxy-benzoic acid

To a solution of 5-bromo-2-chloro-1-fluoro-3-methoxy-benzene (9.811 g,40.97 mmol) in THF (125 mL) under nitrogen at −78° C. was added LDA (24mL of 2 M in THF/heptane/ethylbenzene, 48 mmol) and the mixture stirredfor 30 minutes. The solution was added to solid carbon dioxide (dry ice)and allowed to warm to room temperature and stirred for 1 hour. Themixture was diluted with water (150 mL) and washed with ethyl acetate(4×). The aqueous layer was then acidified to pH=3 and extracted withethyl acetate (3×75 mL). The combined organic extracts were washed withwater (2×50 mL), dried over MgSO₄, filtered and concentrated in vacuo toprovide 6-bromo-3-chloro-2-fluoro-4-methoxy-benzoic acid (7.91 g, 68%).¹H NMR (500 MHz, DMSO-d₆) δ 14.01 (s, 1H), 7.36 (d, J=1.8 Hz, 1H), 3.95(s, 3H) ppm.

Step 3:3-chloro-2-fluoro-4-methoxy-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoicacid

A solution of 2-methoxy-4-(trifluoromethoxy)phenol (2.289 g, 11.00 mmol)in toluene (100 mL) was bubbled with nitrogen for 10 minutes.6-Bromo-3-chloro-2-fluoro-4-methoxy-benzoic acid (3.006 g, 10.60 mmol),Cs₂CO₃ (6.913 g, 21.22 mmol) and copper (I) iodide (404 mg, 2.12 mmol)were added and the mixture was bubbled with nitrogen for an additional10 minutes. The mixture was heated at 100° C. for 20 hours, and thencooled and partitioned between ethyl acetate and water. The aqueouslayer was separated, acidified to pH=3 with 2 M aqueous HCl, andextracted with ethyl acetate (3×150 mL). The combined organic extractswere dried over MgSO₄, filtered and concentrated in vacuo. The solid wastriturated twice with dichloromethane to provide3-chloro-2-fluoro-4-methoxy-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoicacid (1.187 g, 22%). ESI-MS m z calc. 410.02, found 411.3 (M+1)⁺; 409.5(M−1)⁻; LC/MS retention time (Method F): 0.56 minutes.

Step 4: methyl4-[[3-chloro-2-fluoro-4-methoxy-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxylate

To a solution of3-chloro-2-fluoro-4-methoxy-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoicacid (200 mg, 0.487 mmol) and DMF (4 μL, 0.05 mmol) in dichloromethane(5 mL) at 0° C. was added oxalyl chloride (130 μL, 1.49 mmol). Themixture was warmed to room temperature, stirred for 1 hour and thenconcentrated in vacuo. The residue was redissolved in dichloromethane (3mL) and added to a solution of methyl 4-aminopyridine-2-carboxylate(82.1 mg, 0.540 mmol) and TEA (250 μL, 1.80 mmol) in dichloromethane (3mL) at 0° C. The mixture was warmed to room temperature and stirred for2 hours. The mixture was diluted with dichloromethane (30 mL) and washedwith water (20 mL). The aqueous layer was extracted with additionaldichloromethane (2×20 mL), and the combined organic extracts dried overMgSO₄, filtered and concentrated in vacuo. Silica gel chromatography(0-60% ethyl acetate/heptane) provided methyl4-[[3-chloro-2-fluoro-4-methoxy-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxylate(74 mg, 28%). ESI-MS m z calc. 544.07, found 545.4 (M+1)⁺; 543.4 (M−1)⁻;LC/MS retention time (Method F): 0.94 minutes. ¹H NMR (500 MHz, DMSO-d₆)δ 11.21 (s, 1H), 8.58 (d, J=5.4 Hz, 1H), 8.30 (s, 1H), 7.75 (d, J=5.2Hz, 1H), 7.17 (d, J=8.9 Hz, 1H), 7.12 (d, J=2.7 Hz, 1H), 6.93 (d, J=9.0Hz, 1H), 6.51 (d, J=1.4 Hz, 1H), 3.87 (s, 3H), 3.81 (s, 3H), 3.74 (s,3H) ppm.

Step 5:4-[[3-chloro-2-fluoro-4-methoxy-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(266)

Methyl4-[[3-chloro-2-fluoro-4-methoxy-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxylate(74 mg, 0.14 mmol) was dissolved in a solution of ammonia in methanol (1mL of 7 M, 7 mmol) and stirred at room temperature for 20 hours. Themixture was concentrated in vacuo and the residue partitioned betweenethyl acetate (20 mL) and water (20 mL). The layers were separated andthe aqueous layer extracted with additional ethyl acetate (2×20 mL). Thecombined organic extracts were dried over MgSO₄, filtered andconcentrated in vacuo. The residue was purified by reverse phase HPLC(47-95% acetonitrile/0.1% ammonium hydroxide) to provide4-[[3-chloro-2-fluoro-4-methoxy-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(22 mg, 29%). ESI-MS m z calc. 529.07, found 530.5 (M+1)⁺; 528.6 (M−1)⁻;LC/MS retention time (Method E): 3.13 minutes. ¹H NMR (500 MHz, DMSO-d₆)δ 11.16 (s, 1H), 8.51 (d, J=5.4 Hz, 1H), 8.24 (d, J=2.1 Hz, 1H), 8.07(d, J=2.8 Hz, 1H), 7.77 (dd, J=5.5, 2.2 Hz, 1H), 7.62 (d, J=2.9 Hz, 1H),7.19 (d, J=8.8 Hz, 1H), 7.13 (s, 1H), 6.94 (ddd, J=8.8, 2.7, 1.3 Hz,1H), 6.49 (d, J=1.6 Hz, 1H), 3.80 (s, 3H), 3.75 (s, 3H) ppm.

Example 774-[[4-chloro-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]-5-methyl-1-oxido-pyridin-1-ium-2-carboxamide(267)

4-[[4-Chloro-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]-5-methyl-pyridine-2-carboxamide(8.9 mg, 0.017 mmol, see US 2019/0016671, Example 60, which isincorporated by reference) was dissolved in dichloromethane (2 mL) at 0°C. The solution was treated with meta-chloroperoxybenzoic acid (17 mg,0.076 mmol), and then allowed to warm to room temperature and stirredfor 72 hours. The mixture was partitioned between dichloromethane andwater and the phases separated (phase separation cartridge). Thefiltrate was concentrated in vacuo. Purification by reverse phase HPLC(38-53% acetonitrile/0.1% ammonium hydroxide) provided4-[[4-chloro-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]-5-methyl-1-oxido-pyridin-1-ium-2-carboxamide(6 mg, 62%). ESI-MS m z calc. 529.07, found 530.4 (M+1)⁺; 528.3 (M−1)⁻;LC/MS retention time: 3.01 minutes (Method E). ¹H NMR (500 MHz, CDCl₃) δ10.83 (s, 1H), 9.09 (s, 1H), 8.35 (s, 1H), 8.12 (s, 1H), 7.22 (d, J=8.7Hz, 1H), 6.99-6.90 (m, 3H), 6.46 (t, J=1.6 Hz, 1H), 6.00 (s, 1H), 3.83(s, 3H), 2.23 (d, J=0.8 Hz, 3H) ppm.

Example 784-[[3-chloro-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]-5-methyl-1-oxido-pyridin-1-ium-2-carboxamide(268)

4-[[3-Chloro-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]-5-methyl-pyridine-2-carboxamide(22.5 mg, 0.0434 mmol, see US 2019/0016671, Example 38, which isincorporated by reference) was dissolved in dichloromethane (4.5 mL) andcooled to 0° C. The solution was treated with meta-chloroperoxybenzoicacid (40 mg, 0.18 mmol) and the mixture brought to room temperature andstirred for 72 hours. The mixture was partitioned betweendichloromethane and water and the phases separated (phase separationcartridge). The filtrate was concentrated in vacuo and the residuepurified by reverse phase HPLC (38-53% acetonitrile/0.1% ammoniumhydroxide) to provide4-[[3-chloro-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]-5-methyl-1-oxido-pyridin-1-ium-2-carboxamide(14 mg, 61%). ESI-MS m z calc. 529.07, found 530.4 (M+1)⁺; 528.4 (M−1)⁻;LC/MS retention time (Method E): 2.96 minutes. ¹H NMR (500 MHz, CDCl₃) δ10.85 (s, 1H), 9.06 (s, 1H), 8.33 (s, 1H), 8.12 (s, 1H), 7.35 (dd,J=9.1, 7.8 Hz, 1H), 7.20 (d, J=8.7 Hz, 1H), 6.94-6.89 (m, 2H), 6.45 (dd,J=9.1, 1.5 Hz, 1H), 6.03 (s, 1H), 3.80 (s, 3H), 2.27-2.23 (m, 3H) ppm.

Example 794-[[2-cyano-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(269)

A suspension of4-[[2-bromo-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(600 mg, 0.990 mmol, see Example 40), CuCN (178 mg, 1.99 mmol) andPd(PPh₃)₄ (172 mg, 0.150 mmol) in DMF (10 mL) was bubbled with nitrogenfor 5 minutes in a pressure tube. The tube was sealed and the mixturewas heated at 150° C. for 1 hour. The mixture was diluted with ethylacetate (250 mL) and solids removed by filtration. The filtrate waswashed with water (2×100 mL) and brine, dried over anhydrous MgSO₄ andfiltered and concentrated in vacuo. The residue was purified by reversephase HPLC (Higgins Analytical C18 column, 30×100 mm, 15-75%acetonitrile/5 mM HCl over 30 minutes, flowrate=40 mL/min) to provide4-[[2-cyano-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamidehydrochloride (53.1 mg, 9%) as a white powder. ESI-MS m z calc. 540.09,found 541.3 (M+1)⁺; LC/MS retention time (Method Q): 2.52 minutes. ¹HNMR (500 MHz, DMSO-d₆) δ 11.60 (s, 1H), 8.60 (d, J=5.5 Hz, 1H), 8.35 (d,J=2.1 Hz, 1H), 8.15 (d, J=2.8 Hz, 1H), 8.02 (d, J=9.0 Hz, 1H), 7.86 (dd,J=5.5, 2.2 Hz, 1H), 7.71 (d, J=2.9 Hz, 1H), 7.41 (d, J=8.8 Hz, 1H), 7.29(d, J=2.8 Hz, 1H), 7.21 (d, J=9.0 Hz, 1H), 7.10-7.04 (m, 1H), 3.79 (s,3H) ppm.

Example 805-[[5-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-methyl-2-(trifluoromethyl)pyridine-4-carbonyl]amino]pyrimidine-2-carboxamide(270)

Step 1:5-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-methyl-2-(trifluoromethyl)pyridine-4-carboxylicacid

To a solution of3-fluoro-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine-4-carboxylicacid (0.80 g, 1.9 mmol, see US 2019/0016671, Example 12, Steps 1-3,which is incorporated by reference) in THF (4.0 mL) was slowly addedbromo(methyl)magnesium (1.1 mL, 9.5 mmol) under nitrogen atmosphere. Theresulting mixture was stirred at room temperature for 30 minutes thenheated to 55° C. for 18 hours. The mixture was allowed to cool to roomtemperature and additional bromo(methyl)magnesium (1.1 mL, 9.5 mmol) wasslowly added. The resulting mixture was stirred at 55° C. for anadditional 18 hours. The mixture was diluted with 1 M aqueous HCl andextracted with ethyl acetate (3×). The combined organic layers wereconcentrated in vacuo and purified by reverse phase HPLC (10-99%acetonitrile/5 mM HCl) to provide5-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-methyl-2-(trifluoromethyl)pyridine-4-carboxylicacid (120.5 mg, 15%) as a white solid. ESI-MS m z calc. 411.05, found412.0 (M+1)⁺; LC/MS retention time (Method B): 1.75 minutes. ¹H NMR (400MHz, DMSO-d₆) δ 14.31 (s, 1H), 7.96 (s, 1H), 7.37-7.18 (m, 2H),7.07-6.92 (m, 1H), 3.81 (s, 3H), 2.42 (d, J=1.9 Hz, 3H) ppm.

Step 2: methyl5-[[5-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-methyl-2-(trifluoromethyl)pyridine-4-carbonyl]amino]pyrimidine-2-carboxylate

To a solution of5-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-methyl-2-(trifluoromethyl)pyridine-4-carboxylicacid (33 mg, 0.08 mmol) and DMF (6 μL, 0.08 mmol) in dichloromethane(660 μL) at 0° C. was slowly added oxalyl dichloride (61 mg, 42 μL, 0.48mmol) and the mixture stirred at room temperature for 30 minutes. Thesolvent was removed in vacuo. The resulting acid chloride was dissolvedin NMP (165 μL) added to a solution of methyl5-aminopyrimidine-2-carboxylate (37 mg, 0.24 mmol) and DIEA (62 mg, 84μL, 0.48 mmol) in NMP (165 μL) at 0° C. The mixture was stirred at roomtemperature for 16 hours, and then filtered and purified by reversephase HPLC (1-99% acetonitrile/5 mM HCl) to provide methyl5-[[5-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-methyl-2-(trifluoromethyl)pyridine-4-carbonyl]amino]pyrimidine-2-carboxylate(26 mg, 59%). ESI-MS m z calc. 546.10, found 547.0 (M+1)⁺; LC/MSretention time (Method A): 0.43 minutes.

Step 3:5-[[5-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-methyl-2-(trifluoromethyl)pyridine-4-carbonyl]amino]pyrimidine-2-carboxamide(270)

Methyl5-[[5-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-methyl-2-(trifluoromethyl)pyridine-4-carbonyl]amino]pyrimidine-2-carboxylate(25 mg, 0.046 mmol) was dissolved in a solution of ammonia in methanol(800 μL of 7 M, 5.6 mmol) and stirred at room temperature for 18 hours.The solvent was removed in vacuo. The residue was dissolved in DMSO,filtered and purified by reverse phase HPLC (10-99% acetonitrile/5 mMHCl) to provide5-[[5-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-methyl-2-(trifluoromethyl)pyridine-4-carbonyl]amino]pyrimidine-2-carboxamide(21.0 mg, 86%). ESI-MS m z calc. 531.10, found 532.1 (M+1)⁺; LC/MSretention time (Method C): 2.18 minutes. ¹H NMR (400 MHz, DMSO-d₆) δ11.53 (s, 1H), 9.18 (s, 2H), 8.16-8.09 (m, 1H), 8.07 (s, 1H), 7.78-7.69(m, 1H), 7.35 (d, J=8.8 Hz, 1H), 7.23 (d, J=2.7 Hz, 1H), 7.01 (ddd,J=8.9, 2.7, 1.3 Hz, 1H), 3.79 (s, 3H), 2.47 (d, J=2.0 Hz, 3H) ppm.

Example 81N-(2-carbamoyl-5-methyl-4-pyridyl)-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-methyl-2-(trifluoromethyl)pyridine-4-carboxamide(271)

Step 1: methyl4-[[5-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-methyl-2-(trifluoromethyl)pyridine-4-carbonyl]amino]-5-methyl-pyridine-2-carboxylate

A solution of5-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-methyl-2-(trifluoromethyl)pyridine-4-carboxylicacid (20 mg, 0.049 mmol, see Example 80 above, Step 4) and DMF (4 μL,0.05 mmol) in dichloromethane at 0° C. was treated with oxalyldichloride (37 mg, 26 μL, 0.29 mmol) dropwise and the resulting mixturestirred at room temperature for 20 minutes. The mixture was concentratedin vacuo. The resulting acid chloride was dissolved in NMP and added toa solution of methyl 4-amino-5-methyl-pyridine-2-carboxylate (24 mg,0.15 mmol, Preparation 1) and DIEA (38 mg, 51 μL, 0.29 mmol) in NMP. Themixture was stirred at room temperature for 16 hours, and then filteredand purified by reverse phase HPLC (30-99% acetonitrile/5 mM HCl) toprovide methyl4-[[5-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-methyl-2-(trifluoromethyl)pyridine-4-carbonyl]amino]-5-methyl-pyridine-2-carboxylate(10.6 mg, 39%). ESI-MS m z calc. 559.12, found 560.1 (M+1)⁺; LC/MSretention time (Method C): 2.55 minutes.

Step 2:N-(2-carbamoyl-5-methyl-4-pyridyl)-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-methyl-2-(trifluoromethyl)pyridine-4-carboxamide(271)

Methyl4-[[5-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-methyl-2-(trifluoromethyl)pyridine-4-carbonyl]amino]-5-methyl-pyridine-2-carboxylate(10 mg, 0.018 mmol) was dissolved in a solution of ammonia in methanol(1.2 mL of 7 M, 8.4 mmol) and stirred at room temperature for 18 hours.The mixture was concentrated in vacuo. The residue was dissolved inDMSO, filtered and purified by reverse phase HPLC (1-99% acetonitrile/5mM HCl) to provideN-(2-carbamoyl-5-methyl-4-pyridyl)-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-methyl-2-(trifluoromethyl)pyridine-4-carboxamide(6.0 mg, 62%) as a white solid. ESI-MS m z calc. 544.12, found 545.1(M+1)⁺; LC/MS retention time (Method C): 2.35 minutes. ¹H NMR (400 MHz,DMSO-d₆) δ 10.59 (s, 1H), 8.49 (d, J=6.6 Hz, 2H), 8.07 (s, 1H), 8.01 (s,1H), 7.62 (s, 1H), 7.34 (d, J=8.8 Hz, 1H), 7.26 (d, J=2.7 Hz, 1H), 7.04(d, J=8.7 Hz, 1H), 3.82 (s, 3H), 2.31 (s, 3H), 2.07 (s, 3H) ppm.

Example 82N-(2-carbamoyl-5-methyl-4-pyridyl)-2-methoxy-4-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-(trifluoromethyl)pyridine-3-carboxamide(272)

Step 1: 2-methoxy-6-(trifluoromethyl)pyridine-3-carboxylic acid

To the a stirring solution of sodium methoxide (2.9 g, 54 mmol) inmethanol (24 mL) at 0° C. was added a solution of2-chloro-6-(trifluoromethyl)pyridine-3-carboxylic acid (3.0 g, 13 mmol)in methanol (6 mL). The mixture was refluxed for 16 hours, and thencooled and diluted with water (10 mL) and dichloromethane (50 mL). Themixture acidified with 2 M aqueous HCl at 0° C. The organic layer wasseparated, dried over MgSO₄, filtered and concentrated in vacuo toprovide 2-methoxy-6-(trifluoromethyl)pyridine-3-carboxylic acid (2.6 g,88%) as a light yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 8.59 (d, J=8 Hz,1H), 7.46 (d, J=8 Hz, 1H), 4.23 (s, 3H) ppm. The acid proton was absent.ESI-MS m z calc. 221.03, found 220.0 (M−1)⁻; LC/MS retention time(Method R): 1.27 minutes.

Step 2: 4-chloro-2-methoxy-6-(trifluoromethyl)pyridine-3-carboxylic acid

To a stirring solution of 2,2,6,6-tetramethylpiperidine (7.0 g, 49.6mmol) in THF (40 mL) at −50° C. was added n-butyllithium (28 mL of 1.8M, 50.4 mmol) and the mixture stirred for 10 minutes. The solution wascooled to −78° C. and treated with a solution of2-methoxy-6-(trifluoromethyl)pyridine-3-carboxylic acid (2.5 g, 11 mmol)in THF (40 mL). The mixture was stirred at −78° C. for 2 hours, and thentransferred to a solution of hexachloroethane (12.0 g, 50.7 mmol) in THF(40 mL) at −50° C. The mixture was gradually warmed to room temperatureand stirred for 1 hour. The mixture was washed with 2 M aqueous HCl(4×). The organic layer separated, dried over MgSO₄, filtered andconcentrated in vacuo. Purification by silica gel chromatography (5-20%ethyl acetate/hexane) provided4-chloro-2-methoxy-6-(trifluoromethyl)pyridine-3-carboxylic acid (2.1 g,63%). ¹H NMR (400 MHz, CDCl₃) δ 7.25 (s, 1H), 3.95 (s, 3H) ppm. The acidproton was absent. ESI-MS m z calc. 254.99, found 254.2 (M−1)⁻; LC/MSretention time (Method R): 1.36 minutes.

Step 3: methyl4-chloro-2-methoxy-6-(trifluoromethyl)pyridine-3-carboxylate

A solution of4-chloro-2-methoxy-6-(trifluoromethyl)pyridine-3-carboxylic acid (3.23g, 12.6 mmol) in DMF (30 mL) was treated with sodium carbonate (2.78 g,26.2 mmol) followed by methyl iodide (5.43 g, 38.3 mmol). The mixturewas stirred at room temperature overnight, then diluted with ethylacetate and washed with saturated aqueous NaHCO₃ (3×) and brine. Theorganic layer was separated, dried over MgSO₄, filtered and concentratedin vacuo to provide methyl4-chloro-2-methoxy-6-(trifluoromethyl)pyridine-3-carboxylate (2.68 g,79%). ¹H NMR (400 MHz, DMSO-d₆) δ 7.88 (s, 1H), 3.98 (s, 3H), 3.93 (s,3H) ppm.

Step 4: methyl2-methoxy-4-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-(trifluoromethyl)pyridine-3-carboxylate

A mixture of methyl4-chloro-2-methoxy-6-(trifluoromethyl)pyridine-3-carboxylate (2.68 g,9.94 mmol), K₂CO₃ (1.82 g, 13.2 mmol) and2-methoxy-4-(trifluoromethoxy)phenol (2.18 g, 10.5 mmol) in acetonitrile(15 mL) was heated in a pressure vessel at 90° C. for 8 hours. Themixture was diluted with ethyl acetate and washed with 2 M aqueous NaOH(2×). The organic layer was separated, dried over MgSO₄, filtered andconcentrated to provide methyl2-methoxy-4-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-(trifluoromethyl)pyridine-3-carboxylate(3.9 g, 89%). ESI-MS m z calc. 441.07, found 442.1 (M+1)⁺; LC/MSretention time (Method F): 1.08 minutes.

Step 5:2-methoxy-4-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-(trifluoromethyl)pyridine-3-carboxylicacid

A solution of methyl2-methoxy-4-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-(trifluoromethyl)pyridine-3-carboxylate(3.9 g, 8.8 mmol) in THF (20 mL) was treated with 2 M aqueous NaOH (34mL of 2 M, 68 mmol). The mixture was heated at 50° C. for 20 hours.Additional aqueous NaOH (13 mL of 2 M, 26 mmol) was added and themixture refluxed for 7 hours. The mixture was allowed to cool andacidified with 4 M aqueous HCl to pH=4. The organic layer was separated,dried over MgSO₄, filtered and concentrated in vacuo to provide2-methoxy-4-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-(trifluoromethyl)pyridine-3-carboxylicacid (3.92 g, 104%). ESI-MS m z calc. 427.05, found 428.4 (M+1)⁺; LC/MSretention time (Method F): 0.59 minutes.

Step 6:N-(2-carbamoyl-5-methyl-4-pyridyl)-2-methoxy-4-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-(trifluoromethyl)pyridine-3-carboxamide(272)

A solution of2-methoxy-4-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-(trifluoromethyl)pyridine-3-carboxylicacid (400 mg, 0.936 mmol) in dichloromethane (10 mL) was treated withDMF (5 μL, 0.07 mmol) and oxalyl chloride (160 μL, 1.83 mmol) andstirred at room temperature for 1 hour before concentrating. The residuewas redissolved in dichloromethane (10 mL) and treated with TEA (400 μL,2.87 mmol) followed by methyl 4-amino-5-methyl-pyridine-2-carboxylate(17.3 mg, 0.104 mmol, Preparation 1). The mixture was stirred at roomtemperature for 2 hours. The mixture was then concentrated, treated witha solution of ammonia in methanol (5 mL of 7 M, 35 mmol) and stirred atroom temperature for 20 hours. The mixture was concentrated in vacuo.Purification by reverse phase HPLC 38-53% acetonitrile/0.1% ammoniumhydroxide), followed by additional reverse phase HPLC purification(0-100% acetonitrile/0.05% trifluoroacetic acid) providedN-(2-carbamoyl-5-methyl-4-pyridyl)-2-methoxy-4-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-(trifluoromethyl)pyridine-3-carboxamide(82.3 mg, 15%). ESI-MS m z calc. 560.11, found 561.4 (M+1)⁺; LC/MSretention time (Method E): 3.34 minutes. ¹H NMR (500 MHz, DMSO-d₆) δ10.31 (s, 1H), 8.54 (s, 1H), 8.45 (s, 1H), 8.04 (d, J=2.8 Hz, 1H), 7.58(d, J=2.8 Hz, 1H), 7.38 (d, J=8.8 Hz, 1H), 7.28 (d, J=2.7 Hz, 1H), 7.05(ddt, J=8.9, 2.5, 1.3 Hz, 1H), 6.70 (s, 1H), 4.00 (s, 3H), 3.82 (s, 3H),2.31 (s, 3H) ppm.

Example 833-methoxy-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]-N-[2-(methylcarbamoyl)-4-pyridyl]-2-(trifluoromethyl)pyridine-4-carboxamide(273)

Step 1: methyl4-[[3-methoxy-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine-4-carbonyl]amino]pyridine-2-carboxylate

A solution of3-fluoro-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine-4-carboxylicacid (625 mg, 1.51 mmol, see Example 80, Step 3) in dichloromethane (18mL) at 0° C. under nitrogen was treated with DMF (10 μL, 0.13 mmol)followed by oxalyl chloride (175 μL, 2.01 mmol). The mixture was allowedto warm to room temperature over 40 minutes before concentrating. Theacid chloride was redissolved in dichloromethane, treated with methyl4-aminopyridine-2-carboxylate (278 mg, 1.83 mmol) and TEA (420 μL, 3.01mmol), and stirred at room temperature for 16 hours. The mixture wasdiluted with saturated aqueous NaHCO₃ and the layers separated. Theorganic layer was dried over MgSO₄, filtered and concentrated. Theresidue was then dissolved in methanol (6 mL) and TEA (2 mL, 14 mmol)and heated at 70° C. for 4 hours. The mixture was allowed to cool andwas then concentrated. Silica gel chromatography (0-55% ethylacetate/heptane) provided methyl4-[[3-methoxy-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine-4-carbonyl]amino]pyridine-2-carboxylate(380 mg, 45%). ESI-MS m z calc. 561.10, found 562.4 (M+1)⁺; LC/MSretention time (Method F): 0.93 minutes.

Step 2:3-methoxy-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]-N-[2-(methylcarbamoyl)-4-pyridyl]-2-(trifluoromethyl)pyridine-4-carboxamide(273)

A solution of methyl4-[[3-methoxy-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine-4-carbonyl]amino]pyridine-2-carboxylate(20 mg, 0.036 mmol) in methanol (150 μL) was treated with a solution ofmethylamine in water (200 μL of 40% w/v, 2.576 mmol). The mixture wasstirred for 40 minutes, and then purified directly by reverse phase HPLC(47-95% acetonitrile/0.1% ammonium hydroxide) to provide3-methoxy-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]-N-[2-(methylcarbamoyl)-4-pyridyl]-2-(trifluoromethyl)pyridine-4-carboxamide(10.2 mg, 46%). ESI-MS m z calc. 560.11, found 561.5 (M+1)⁺; LC/MSretention time (Method E): 3.28 minutes. ¹H NMR (500 MHz, DMSO-d₆) δ11.49 (s, 1H), 8.76 (q, J=4.8 Hz, 1H), 8.57 (d, J=5.5 Hz, 1H), 8.29 (d,J=2.1 Hz, 1H), 7.97 (s, 1H), 7.84 (dd, J=5.5, 2.2 Hz, 1H), 7.36 (d,J=8.8 Hz, 1H), 7.23 (d, J=2.7 Hz, 1H), 7.01 (ddd, J=8.7, 2.7, 1.3 Hz,1H), 3.96 (s, 3H), 3.80 (s, 3H), 2.83 (d, J=4.9 Hz, 3H) ppm.

Example 84N-(2-carbamoyl-4-pyridyl)-6-ethyl-3-[2-methoxy-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-2-carboxamide(274)

Step 1: methyl3-[2-methoxy-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)-6-vinyl-pyridine-2-carboxylate

A mixture of methyl6-chloro-3-[2-methoxy-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-2-carboxylate(230 mg, 0.516 mmol, see Example 58, Step 4), potassiumvinyltrifluoroborate (84 mg, 0.63 mmol), Pd(dppf)Cl₂ (27 mg, 0.037 mmol)and TEA (100 μL, 0.718 mmol) in 2-propanol (4.5 mL) was heated at 90° C.for 1 hour. The mixture was diluted with water (20 mL) and extractedwith ethyl acetate (3×20 mL). The combined organic extracts were driedover MgSO₄, filtered and concentrated in vacuo to provide methyl3-[2-methoxy-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)-6-vinyl-pyridine-2-carboxylate(205 mg, 91%). ESI-MS m z calc. 437.07, found 438.5 (M+1)⁺; LC/MSretention time (Method F): 1.05 minutes.

Step 2: methyl6-ethyl-3-[2-methoxy-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-2-carboxylate

A solution of methyl3-[2-methoxy-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)-6-vinyl-pyridine-2-carboxylate(200 mg, 0.457 mmol) in ethanol (5 mL) was stirred with 10% palladium oncarbon (201 mg) under hydrogen atmosphere at room temperature for 20hours. The mixture was filtered through Celite and the filtrateconcentrated in vacuo to provide methyl6-ethyl-3-[2-methoxy-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-2-carboxylate(159 mg, 79%). ESI-MS m z calc. 439.09, found 440.5 (M+1)⁺; LC/MSretention time (Method F): 1.05 minutes. ¹H NMR (500 MHz, CDCl₃) δ 7.28(s, 1H), 7.10-7.02 (m, 1H), 6.85 (d, J=11.6 Hz, 2H), 3.97 (s, 3H), 3.80(s, 3H), 2.98 (d, J=8.0 Hz, 2H), 1.33 (t, J=6.8 Hz, 3H) ppm.

Step 3:6-ethyl-3-[2-methoxy-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-2-carboxylicacid

To a solution of methyl6-ethyl-3-[2-methoxy-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-2-carboxylate(157 mg, 0.357 mmol) in THF (3 mL) was added 2 M aqueous NaOH (3 mL of 2M, 6 mmol) and the mixture stirred at room temperature for 1 hour. Themixture was acidified to pH=3 with 2 M aqueous HCl and extracted withethyl acetate (4×). The combined organic extracts were dried over MgSO₄,filtered and concentrated in vacuo to provide6-ethyl-3-[2-methoxy-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-2-carboxylicacid (150 mg, 99%). ESI-MS m z calc. 425.07, found 426.5 (M+1)⁺; 424.6(M−1)⁻; LC/MS retention time (Method F): 0.59 minutes.

Step 4:N-(2-carbamoyl-4-pyridyl)-6-ethyl-3-[2-methoxy-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-2-carboxamide(274)

To a solution of6-ethyl-3-[2-methoxy-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-2-carboxylicacid (50 mg, 0.12 mmol) in dichloromethane (1 mL) and DMF (1 μL, 0.013mmol) at 0° C. was added oxalyl chloride (40 μL, 0.46 mmol) and themixture was warmed to room temperature and stirred for 30 minutes. Themixture was concentrated in vacuo. The acid chloride was redissolved indichloromethane (1 mL) and added to a solution of methyl4-aminopyridine-2-carboxylate (18 mg, 0.12 mmol) and TEA (50 μL, 0.36mmol) in dichloromethane (1 mL) at 0° C. The mixture was warmed to roomtemperature and stirred for 1 hour. The mixture was partitioned betweendichloromethane (20 mL) and water (25 mL) and the layers separated. Theaqueous layer extracted with additional dichloromethane (2×20 mL), andthe combined organic extracts were dried and concentrated in vacuo. Thecrude product was treated with a solution of ammonia in methanol (1 mLof 7 M, 7 mmol) and stirred for 6 hours at room temperature. The mixturewas concentrated in vacuo and purified by reverse phase HPLC (47-95%acetonitrile/0.1% ammonium hydroxide) to provideN-(2-carbamoyl-4-pyridyl)-6-ethyl-3-[2-methoxy-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-2-carboxamide(10 mg, 16%). ESI-MS m z calc. 544.12, found 545.3 (M+1)⁺; 543.6 (M−1)⁻;LC/MS retention time (Method E): 3.52 minutes. ¹H NMR (500 MHz, DMSO-d₆)δ 11.16 (s, 1H), 8.55 (dd, J=5.5, 0.6 Hz, 1H), 8.36 (d, J=2.2 Hz, 1H),8.09 (d, J=2.8 Hz, 1H), 7.90 (dd, J=5.5, 2.2 Hz, 1H), 7.64 (d, J=2.8 Hz,1H), 7.53 (s, 1H), 7.25 (d, J=8.8 Hz, 1H), 7.20 (d, J=2.8 Hz, 1H), 6.98(ddt, J=8.7, 2.3, 1.2 Hz, 1H), 3.77 (s, 3H), 3.00-2.86 (m, 2H), 1.31 (t,J=7.4 Hz, 3H) ppm.

Example 85N-(2-carbamoyl-4-pyridyl)-6-methoxy-3-[2-methoxy-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-2-carboxamide(275)

Step 1: methyl 1-oxido-5-(trifluoromethyl)pyridin-1-ium-2-carboxylate

Urea hydrogen peroxide (31.37 g, 323.5 mmol) was added portion-wise to astirring solution of methyl 5-(trifluoromethyl)pyridine-2-carboxylate(20.0 g, 95.6 mmol) in DCE (150 mL) at 0° C. Trifluoroacetic anhydride(54 g, 36 mL, 254 mmol) was then added over 30 minutes at −10° C. Themixture was stirred for an additional 30 minutes at 0° C. and thenallowed to warm to room temperature and stirred for 1 hour. The mixturewas then poured into ice-cold 0.5 M aqueous HCl (320 mL). The mixturewas diluted with dichloromethane (160 mL) and layers were separated. Theaqueous phase was extracted with additional dichloromethane (2×160 mL).The combined organic extracts were washed with water (2×300 mL) andbrine (200 mL), dried over anhydrous Na₂SO₄, filtered and concentratedin vacuo to provide methyl1-oxido-5-(trifluoromethyl)pyridin-1-ium-2-carboxylate (20.65 g, 98%) aslight yellow solid. ESI-MS m z calc. 221.03, found 222.1 (M+1)⁺; LC/MSretention time (Method L): 1.26 minutes. ¹H NMR (300 MHz, CDCl₃) δ 8.51(s, 1H), 7.74 (d, J=8.2 Hz, 1H), 7.47 (d, J=8.2 Hz, 1H), 4.04 (s, 3H)ppm. ¹⁹F NMR (282 MHz, CDCl₃) δ −63.61 (s, 3F) ppm.

Step 2: methyl 6-hydroxy-5-(trifluoromethyl)pyridine-2-carboxylate

Trifluoroacetic anhydride (292 g, 193 mL, 1.39 mol) was added dropwiseto a solution of methyl1-oxido-5-(trifluoromethyl)pyridin-1-ium-2-carboxylate (51.06 g, 230.7mmol) in DMF (305 mL) at 0° C. The mixture was stirred at roomtemperature overnight, then concentrated in vacuo to remove excesstrifluoroacetic acid. The residual DMF solution was poured dropwise intostirring water (1000 mL) at 0° C. The resulting precipitate wascollected by filtration. The solid was washed with water (300 mL) anddried under high vacuum to provide methyl6-hydroxy-5-(trifluoromethyl)pyridine-2-carboxylate (45.24 g, 86%) aswhite solid. ESI-MS m z calc. 221.03, found 222.1 (M+1)⁺; LC/MSretention time (Method L): 1.43 minutes. ¹H NMR (300 MHz, DMSO-d₆) δ7.90 (d, J=7.2 Hz, 1H), 7.03 (d, J=7.2 Hz, 1H), 4.02 (s, 3H) ppm. ¹⁹FNMR (282 MHz, DMSO-d₆) δ −66.39 (s, 3F) ppm.

Step 3: methyl3-bromo-6-hydroxy-5-(trifluoromethyl)pyridine-2-carboxylate

N-Bromosuccinimide (18.3 g, 104 mmol) was added in three equal portionsover 45 minutes to a solution of methyl6-hydroxy-5-(trifluoromethyl)pyridine-2-carboxylate (20.6 g, 93.2 mmol)in DMF (160 mL). A slight exotherm was observed during the NBS addition.The mixture was stirred at room temperature for 60 minutes, then dilutedwith water (1 L) and the resulting precipitate collected by filtration.The solid was washed with water (3×100 mL) and dried under high vacuumto provide methyl3-bromo-6-hydroxy-5-(trifluoromethyl)pyridine-2-carboxylate (26.61 g,95%) as a white powder. ESI-MS m z calc. 298.94, found 300.0 (M+1)⁺;LC/MS retention time (Method L): 1.64 minutes. ¹H NMR (300 MHz, CDCl₃) δ4.03 (s, 3H), 7.98 (s, 1H), 11.53 (br s, 1H) ppm. ¹⁹F NMR (282 MHz,CDCl₃) δ −66.4 (s, 3F) ppm.

Step 4: methyl3-bromo-6-methoxy-5-(trifluoromethyl)pyridine-2-carboxylate

A mixture of methyl3-bromo-6-hydroxy-5-(trifluoromethyl)pyridine-2-carboxylate (2.4 g, 8.0mmol), iodomethane (3.4 g, 1.5 mL, 24 mmol) and silver carbonate (2.7 g,9.8 mmol) in dioxane (35 mL) was heated at 50° C. in a sealed tubeovernight. The mixture was filtered through Celite and the solids washedwith ethyl acetate (150 mL). The filtrate was concentrated in vacuo. Theresidue was purified using silica gel chromatography (0-50% ethylacetate/heptane) to provide methyl3-bromo-6-methoxy-5-(trifluoromethyl)pyridine-2-carboxylate (2.25 g,90%). ESI-MS m z calc. 312.96, found 314.0 (M+1)⁺; LC/MS retention time(Method L): 2.1 minutes. ¹H NMR (300 MHz, CDCl₃) δ 4.00 (s, 3H), 4.05(s, 3H), 8.06 (s, 1H) ppm. ¹⁹F NMR (282 MHz, CDCl₃) δ −64.4 (s, 3F) ppm.

Step 5: 3-bromo-6-methoxy-5-(trifluoromethyl)pyridine-2-carboxylic acid

To a solution of methyl3-bromo-6-methoxy-5-(trifluoromethyl)pyridine-2-carboxylate (9.2 g, 29mmol) in 2-propanol (270 mL) was added NaOH (7.11 g, 178 mmol) and themixture stirred at room temperature for 1 hour. The mixture was dilutedwith 3 M aqueous HCl (49 mL) then partially concentrated in vacuo toremove isopropanol. Additional 3 M aqueous HCl (10 mL) was added and theresulting solid collected by filtration and washed with water (150 mL).The solid was dissolved in ethyl acetate and washed with 0.1 M aqueousHCl (100 mL). The organic phase was dried over anhydrous Na₂SO₄,filtered and concentrated in vacuo to provide3-bromo-6-methoxy-5-(trifluoromethyl)pyridine-2-carboxylic acid (6.73 g,76%) as a white solid. ESI-MS m z calc. 298.94, found 300.0 (M+1)⁺;LC/MS retention time (Method M): 2.43 minutes. ¹H NMR (300 MHz, CDCl₃) δ4.09 (s, 3H), 6.18 (br. s., 1H), 8.18 (s, 1H) ppm. ¹⁹F NMR (282 MHz,CDCl₃) δ −64.4 (s, 3F) ppm.

Step 6: methyl4-[[3-bromo-6-methoxy-5-(trifluoromethyl)pyridine-2-carbonyl]amino]pyridine-2-carboxylate

DMF (10 μL, 0.13 mmol) was added to a solution of3-bromo-6-methoxy-5-(trifluoromethyl)pyridine-2-carboxylic acid (167 mg,0.557 mmol) and oxalyl chloride (200 μL, 2.29 mmol) in dichloromethane(5 mL) at 0° C. and the resulting mixture stirred at room temperaturefor 2 hours. The solvent was removed in vacuo and the acid chlorideredissolved in dichloromethane (5 mL). Methyl4-aminopyridine-2-carboxylate (90 mg, 0.59 mmol) and TEA (180 μL, 1.29mmol) were added and the resulting mixture stirred at room temperaturefor 2 hours. The mixture was concentrated in vacuo and purified bysilica gel chromatography (0-70% ethyl acetate/petroleum ether) toprovide methyl4-[[3-bromo-6-methoxy-5-(trifluoromethyl)pyridine-2-carbonyl]amino]pyridine-2-carboxylate(127 mg, 53%) as a pale yellow solid. ESI-MS m z calc. 432.99, found434.4 (M+1)⁺; 432.5 (M−1)⁻; LC/MS retention time (Method F): 0.81minutes. ¹H NMR (500 MHz, DMSO-d₆) δ 11.29 (s, 1H), 8.67 (d, J=5.4 Hz,1H), 8.56 (s, 1H), 8.44 (d, J=2.1 Hz, 1H), 7.91 (dd, J=5.4, 2.2 Hz, 1H),4.07 (s, 3H), 3.91 (s, 3H) ppm.

Step 7: methyl4-[[6-methoxy-3-[2-methoxy-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-2-carbonyl]amino]pyridine-2-carboxylate

A mixture of 2-methoxy-4-(trifluoromethoxy)phenol (291 mg, 0.140 mmol),methyl4-[[3-bromo-6-methoxy-5-(trifluoromethyl)pyridine-2-carbonyl]amino]pyridine-2-carboxylate(55 mg, 0.13 mmol), Cs₂CO₃ (63 mg, 0.19 mmol) and copper (I) iodide (5.3mg, 0.028 mmol) in toluene (2 mL) was heated under nitrogen at 100° C.for 60 hours. The mixture was diluted with water (20 mL) and extractedwith ethyl acetate (3×25 mL). The combined organic extracts were driedover MgSO₄, filtered and concentrated in vacuo. The residue was purifiedby silica gel chromatography (0-60% ethyl acetate/heptane) to providemethyl4-[[6-methoxy-3-[2-methoxy-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-2-carbonyl]amino]pyridine-2-carboxylate(9 mg, 13%). ESI-MS m z calc. 561.10, found 562.5 (M+1)⁺; 560.5 (M−1)⁻;LC/MS retention time (Method F): 0.96 minutes.

Step 8:N-(2-carbamoyl-4-pyridyl)-6-methoxy-3-[2-methoxy-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-2-carboxamide(275)

Methyl4-[[6-methoxy-3-[2-methoxy-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-2-carbonyl]amino]pyridine-2-carboxylate(9 mg, 0.02 mmol) was dissolved in a solution of ammonia in methanol(200 μL of 7 M, 1.4 mmol) and the mixture stirred at room temperaturefor 20 hours. The mixture was concentrated in vacuo and purified byreverse phase HPLC (47-95% acetonitrile/0.1% ammonium hydroxide) toprovideN-(2-carbamoyl-4-pyridyl)-6-methoxy-3-[2-methoxy-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-2-carboxamide(2 mg, 23%). ESI-MS m z calc. 546.10, found 547.5 (M+1)⁺; 545.6 (M−1)⁻;LC/MS retention time (Method E): 3.38 minutes. ¹H NMR (500 MHz,methanol-d₄) δ 8.59-8.50 (m, 2H), 8.30 (d, J=2.1 Hz, 1H), 8.02 (dd,J=5.5, 2.2 Hz, 1H), 7.60 (s, 1H), 7.15 (d, J=8.8 Hz, 1H), 7.03 (d, J=2.7Hz, 1H), 6.89 (ddd, J=8.8, 2.7, 1.3 Hz, 1H), 4.15 (s, 3H), 3.80 (s, 3H)ppm.

Example 864-[[5-methoxy-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(276)

Step 1: 2-iodo-5-methoxy-4-(trifluoromethyl)benzoic acid

3-Methoxy-4-(trifluoromethyl)benzoic acid (5.02 g, 22.8 mmol), PhI(OAc)₂(11.01 g, 34.18 mmol) and iodine (8.78 g, 34.6 mmol) were combined inDMF (100 mL) and the reaction vessel flushed with nitrogen. Pd(OAc)₂(261 mg, 1.16 mmol) was added and the mixture heated under nitrogen at100° C. for 90 minutes. The mixture was cooled to room temperature andpartitioned between ethyl acetate and water. The layers were separatedand the organic layer washed with additional water (5×). The organiclayer was washed with brine, dried over MgSO₄, filtered and concentratedin vacuo. Silica gel chromatography (0-10% methanol/dichloromethane)provided 2-iodo-5-methoxy-4-(trifluoromethyl)benzoic acid (4.63 g, 59%)as a white solid. ESI-MS m z calc. 345.93, found 345.2 (M−1)⁻; LC/MSretention time (Method F): 0.48 minutes. ¹H NMR (500 MHz, CDCl₃) δ 8.16(d, J=0.8 Hz, 1H), 7.60 (s, 1H), 3.96 (s, 3H) ppm.

Step 2:5-methoxy-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoicacid

2-Iodo-5-methoxy-4-(trifluoromethyl)benzoic acid (4.63 g, 13.4 mmol) and2-methoxy-4-(trifluoromethoxy)phenol (3.05 g, 14.7 mmol) were combinedin toluene (100 mL) and the solution purged with nitrogen(3×vacuum/nitrogen fill). Cs₂CO₃ (6.45 g, 19.8 mmol) was added, and themixture was stirred for 5 minutes. Copper (I) iodide (2.58 g, 13.6 mmol)was added and the mixture again purged with nitrogen. The mixture washeated at 100° C. overnight. Additional copper (I) iodide (1.44 g, 7.56mmol) and 2-methoxy-4-(trifluoromethoxy)phenol (1.7 g, 8.2 mmol) wereadded and the mixture was heated at 100° C. for 5 hours. The mixture wasthen cooled to room temperature, acidified to pH=1 with 1 M aqueous HCland partitioned between ethyl acetate and water. The layers wereseparated, and the aqueous layer was extracted with ethyl acetate (3×).The combined organic extracts were washed with brine, dried over MgSO₄,filtered and concentrated in vacuo. Two sequential silica gelchromatography purifications (0-5% methanol/dichloromethane) provided5-methoxy-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoicacid (1.13 g, 20%). ESI-MS m z calc. 426.05, found 425.4 (M−1)⁻; LC/MSretention time (Method F): 0.65 minutes. ¹H NMR (500 MHz, DMSO-d₆) δ13.44 (s, 1H), 7.57 (s, 1H), 7.16 (d, J=2.5 Hz, 1H), 7.12 (s, 1H),6.93-6.85 (m, 2H), 3.94 (s, 3H), 3.82 (s, 3H) ppm.

Step 3: methyl4-[[5-methoxy-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxylate

A solution of5-methoxy-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoicacid (281 mg, 0.659 mmol) and DMF (5 μL, 0.07 mmol) in dichloromethane(6 mL) at 0° C. was treated with oxalyl chloride (160 μL, 1.83 mmol)then brought to room temperature and stirred for 45 minutes. The mixturewas concentrated in vacuo, redissolved in dichloromethane (4 mL) andadded dropwise to a solution of methyl 4-aminopyridine-2-carboxylate(123 mg, 0.808 mmol) and TEA (280 μL, 2.01 mmol) in dichloromethane (4mL) at 0° C. The mixture was brought to room temperature and stirred for2 hours. The mixture was partitioned between dichloromethane and waterand the phases separated (phase separation cartridge). The organicfiltrate was concentrated in vacuo and purified by silica gelchromatography (0-10% methanol/dichloromethane) to provide methyl4-[[5-methoxy-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxylate(190 mg, 51%) as a white solid. ESI-MS m/z calc. 560.10, found 561.4(M+1)⁺; 559.4 (M−1)⁻; LC/MS retention time (Method F): 0.98 minutes. ¹HNMR (500 MHz, DMSO-d₆) δ 11.08 (s, 1H), 8.59 (d, J=5.4 Hz, 1H), 8.34 (d,J=2.1 Hz, 1H), 7.81 (dd, J=5.5, 2.2 Hz, 1H), 7.58 (s, 1H), 7.16 (s, 1H),7.10 (d, J=2.8 Hz, 1H), 7.06 (d, J=8.8 Hz, 1H), 6.92 (ddd, J=8.7, 2.6,1.2 Hz, 1H), 3.95 (s, 3H), 3.88 (s, 3H), 3.72 (s, 3H) ppm.

Step 4:4-[[5-methoxy-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(276)

Methyl4-[[5-methoxy-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxylate(190 mg, 0.339 mmol) was dissolved in a solution of ammonia in methanol(5 mL of 7 M, 35 mmol) and stirred at room temperature for 8 hours. Themixture was concentrated in vacuo and purified by reverse phase HPLC(47-95% acetonitrile/0.1% ammonium hydroxide) to provide4-[[5-methoxy-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(128 mg, 69%) as a white solid. ESI-MS m z calc. 545.10, found 546.5(M+1)⁺; 544.4 (M−1)⁻; LC/MS retention time (Method E): 3.39 minutes. ¹HNMR (500 MHz, DMSO-d₆) δ 11.02 (s, 1H), 8.52 (d, J=5.5 Hz, 1H), 8.29 (d,J=2.1 Hz, 1H), 8.08 (d, J=2.8 Hz, 1H), 7.82 (dd, J=5.7, 2.2 Hz, 1H),7.63 (d, J=2.8 Hz, 1H), 7.59 (s, 1H), 7.15 (s, 1H), 7.11 (d, J=2.8 Hz,1H), 7.08 (d, J=8.9 Hz, 1H), 6.93 (ddd, J=8.9, 2.8, 1.2 Hz, 1H), 3.96(s, 3H), 3.74 (s, 3H) ppm.

Example 874-[[2-methoxy-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(277)

Step 1: 2,6-difluoro-4-(trifluoromethyl)benzoic acid

To a solution of 1,3-difluoro-5-(trifluoromethyl)benzene (1.0 mL, 10.3mmol) in THF (100 mL) at −78° C. was added LDA (6 mL of 2 M inTHF/heptane/ethylbenzene, 12 mmol) and the mixture stirred at −78° C.for 30 minutes. The mixture was poured into a beaker containing solidcarbon dioxide (dry ice) and allowed to warm to room temperature over 2hours. The mixture was partitioned between ethyl acetate (150 mL) andwater (200 mL) and the layers separated. The aqueous layer was washedwith additional ethyl acetate (150 mL) and then acidified with 2 Maqueous HCl to pH=3. The aqueous layer was extracted with ethyl acetate(3×150 mL), and the combined organic extracts dried over MgSO₄, filteredand concentrated in vacuo to provide2,6-difluoro-4-(trifluoromethyl)benzoic acid (1.023 g, 44%). ¹H NMR (500MHz, DMSO-d₆) δ 14.42 (s, 1H), 7.81-7.74 (m, 2H) ppm.

Step 2: methyl 2,6-difluoro-4-(trifluoromethyl)benzoate

To a solution of 2,6-difluoro-4-(trifluoromethyl)benzoic acid (5.6 g, 25mmol) in methanol (140 mL) was added H₂SO₄ (2 mL, 38 mmol) and themixture heated at 70° C. for 20 hours. Additional H₂SO₄ (1 mL, 19 mmol)was added and mixture was heated for 48 hours. The solution wasconcentrated in vacuo. The residue was dissolved in ethyl acetate (300mL) and washed with NaHCO₃ (2×250 mL) and brine, dried over MgSO₄,filtered and concentrated in vacuo to provide methyl2,6-difluoro-4-(trifluoromethyl)benzoate (4.44 g, 75%). H NMR (500 MHz,DMSO-d₆) δ 7.88-7.81 (m, 2H), 3.94 (s, 3H) ppm.

Step 3:2-methoxy-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoicacid

A mixture of methyl 2,6-difluoro-4-(trifluoromethyl)benzoate (962 mg,4.01 mmol) and Cs₂CO₃ (1.46 g, 4.48 mmol) in DMF (10 mL) was heated at70° C. in a sealed tube and treated portion-wise with2-methoxy-4-(trifluoromethoxy)phenol (840 mg, 4.04 mmol) over 10minutes. The mixture was heated at 70° C. for 10 hours. The mixture wasdiluted with ethyl acetate and washed with 2 M aqueous NaOH and brine(2×). The organic layer was dried over MgSO₄, filtered and concentratedin vacuo to afford crude methyl2-methoxy-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoate.The residue was dissolved in DMF (10 mL), treated with sodium methoxidesolution (8.5 mL of 25% w/v in methanol, 39 mmol) and heated at 50° C.overnight. The mixture was concentrated and partitioned between ethylacetate and 2 M aqueous HCl. The organic layer was separated, dried overMgSO₄, filtered and concentrated. Purification by silica chromatography(0-100% ethyl acetate/heptane) provided2-methoxy-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoicacid (82.8 mg). ESI-MS m z calc. 426.05, found 427.5 (M+1)⁺; LC/MSretention time (Method F): 0.58 minutes.

Step 4:4-[[2-methoxy-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(277)

A solution of2-methoxy-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoicacid (83 mg, 0.19 mmol) in dichloromethane (2 mL) and DMF (5 μL, 0.07mmol) was dropwise treated with oxalyl chloride (120 μL of 2 M, 0.24mmol). The mixture was stirred for 30 minutes then concentrated invacuo. The residue was redissolved in dichloromethane (2 mL) and wastreated with TEA (40 μL, 0.29 mmol) and methyl4-aminopyridine-2-carboxylate (38 mg, 0.25 mmol). The mixture wasstirred overnight then diluted with dichloromethane and washed withsaturated aqueous NaHCO₃. The organic layer was separated, dried overMgSO₄, filtered and concentrated. The residue was dissolved in asolution of ammonia in methanol (5 mL of 7 M, 35 mmol) and stirred atroom temperature for 6 hours. The mixture was concentrated and purifiedby reverse phase HPLC (47-95% acetonitrile/0.1% ammonium hydroxide) toprovide4-[[2-methoxy-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(24.8 mg, 23%). ESI-MS m z calc. 545.10, found 546.5 (M+1)⁺; LC/MSretention time (Method E): 3.26 minutes. ¹H NMR (400 MHz, DMSO-d₆) δ11.12 (s, 1H), 8.51 (d, J=5.5 Hz, 1H), 8.31 (d, J=2.1 Hz, 1H), 8.07 (d,J=2.9 Hz, 1H), 7.81 (dd, J=5.5, 2.2 Hz, 1H), 7.63 (d, J=2.8 Hz, 1H),7.32-7.12 (m, 3H), 7.00 (ddd, J=8.8, 2.7, 1.2 Hz, 1H), 6.56 (d, J=1.3Hz, 1H), 3.94 (s, 3H), 3.78 (s, 3H) ppm.

Example 884-[[2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-methyl-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(278)

Step 1: methyl 2,6-difluoro-3-methyl-4-(trifluoromethyl)benzoate

A solution of LDA (2.1 mL of 2 M in THF/heptane/ethylbenzene, 4.2 mmol)was added dropwise to a solution of methyl2,6-difluoro-4-(trifluoromethyl)benzoate (1000 mg, 4.164 mmol, Example87, Step 2) in THF (8 mL) at −78° C. The mixture was stirred for 10minutes and was then treated with methyl iodide (400 μL, 6.43 mmol). Themixture was stirred at −78° C. for 30 minutes then allowed to warm toroom temperature. The mixture was diluted with water and extracted withethyl acetate (3×). The combined organic extracts were dried over MgSO₄,filtered and concentrated in vacuo. Silica gel chromatography (0-15%ethyl acetate/petroleum ether) provided methyl2,6-difluoro-3-methyl-4-(trifluoromethyl)benzoate (700 mg, 66%,contaminated with residual starting material). The material was taken tothe next step without further purification.

Step 2:2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-methyl-4-(trifluoromethyl)benzoicacid

Methyl 2,6-difluoro-3-methyl-4-(trifluoromethyl)benzoate (700 mg, 2.75mmol), 2-methoxy-4-(trifluoromethoxy)phenol (560 mg, 2.69 mmol) andCs₂CO₃ (1.4 g, 4.3 mmol) were combined in DMF (28 mL) and stirred at 70°C. for 48 hours. The mixture was partitioned between ethyl acetate andbrine and the layers separated. The organic layer was washed with brine,dried over MgSO₄, filtered and concentrated to afford crude methyl2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-methyl-4-(trifluoromethyl)benzoate.The residue was then dissolved in ethanol (5 mL) and aqueous LiOH (1.4mL of 2 M, 2.8 mmol) and the mixture heated at 60° C. overnight. Thesolution was cooled to room temperature and acidified with 2 M aqueousHCl (˜10 mL). The cloudy aqueous mixture was extracted with ethylacetate (2×50 mL), and the combined extracts dried over Na₂SO₄, filteredand concentrated in vacuo to provide2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-methyl-4-(trifluoromethyl)benzoicacid (0.8 g, 68%, contaminated with2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoicacid). ESI-MS m z calc. 428.05, found 427.2 (M−1)⁻; LC/MS retention time(Method E): 0.64 minutes. The material was taken to the next stepwithout further purification.

Step 3:4-[[2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-methyl-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(278)

To a solution of2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-methyl-4-(trifluoromethyl)benzoicacid (1.07 g, 2.50 mmol) and DMF (20 μL, 0.26 mmol) in dichloromethane(25 mL) at 0° C. was added and oxalyl chloride (655 μL, 7.51 mmol)dropwise. The mixture was stirred for 2 hours, and then concentrated invacuo. The acid chloride was redissolved in dichloromethane (25 mL) andadded dropwise to a mixture of methyl 4-aminopyridine-2-carboxylate (540mg, 3.55 mmol) and TEA (2.1 mL, 15 mmol) in dichloromethane (25 mL) at0° C. The resulting mixture was stirred at room temperature overnight.The mixture was concentrated in vacuo, then dissolved in a solution ofammonia in methanol (5 mL of 7 M, 35 mmol) and stirred for 24 hours. Themixture was concentrated and purified by reverse phase HPLC (47-95%acetonitrile/0.1% ammonium hydroxide) to provide4-[[2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-methyl-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(26.4 mg, 2%) as an off-white solid. ESI-MS m z calc. 547.10, found548.1 (M+1)⁺; 546.2 (M−1)⁻; LC/MS retention time (Method E): 3.38minutes. ¹H NMR (400 MHz, CDCl₃) δ 8.85 (s, 1H), 8.56 (d, J=5.6 Hz, 1H),8.40 (dd, J=5.6, 2.3 Hz, 1H), 7.90-7.80 (m, 2H), 7.24 (d, J=9.3 Hz, 1H),6.96 (q, J=2.5 Hz, 2H), 6.82 (s, 1H), 5.53 (s, 1H), 3.95 (s, 3H),2.43-2.37 (m, 3H) ppm.

Example 894-[[5-fluoro-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoyl]amino]-1-oxido-pyridin-1-ium-2-carboxamide(279)

A solution of4-[[5-fluoro-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(50.2 mg, 0.0941 mmol, see US 2019/0016671, Example 42, which isincorporated by reference) in dichloromethane (2 mL) was treated with3-chloroperbenzoic acid (58.9 mg, 0.341 mmol). The mixture was stirredat room temperature for 16 hours, and then diluted with 2 M aqueousNaOH. The organic layer was separated, dried over MgSO₄, filtered andconcentrated. The residue was purified by reverse phase HPLC (38-53%acetonitrile/0.1% ammonium hydroxide) to provide4-[[5-fluoro-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoyl]amino]-1-oxido-pyridin-1-ium-2-carboxamide(10.3 mg, 20%). ESI-MS m z calc. 549.08, found 550.5 (M+1)⁺; LC/MSretention time (Method E): 3.22 minutes. ¹H NMR (400 MHz, DMSO-d₆) δ11.20 (s, 1H), 10.62 (d, J=4.6 Hz, 1H), 8.53 (d, J=3.2 Hz, 1H), 8.37 (d,J=7.1 Hz, 1H), 8.26 (d, J=4.6 Hz, 1H), 7.95 (d, J=10.1 Hz, 1H), 7.84(dd, J=7.2, 3.3 Hz, 1H), 7.30-7.12 (m, 3H), 6.97 (ddd, J=8.9, 2.8, 1.3Hz, 1H), 3.76 (s, 3H) ppm.

Example 904-[[2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethoxy)benzoyl]amino]pyridine-2-carboxamide(280)

Step 1: 6-bromo-2-fluoro-3-(trifluoromethoxy)benzoic acid

To a solution of diisopropylamine (27.7 g, 274 mmol) in THF (262 mL) wasadded a solution of n-butyllithium (105 mL of 2.5 M in hexanes, 262.5mmol) over 45 minutes while maintaining the temperature below −70° C. Atthe end of addition, the yellow solution was stirred for 15 minutes andwarmed to 0° C. and stirred for 10 minutes. The solution was cooled to−70° C. and a solution of 4-bromo-2-fluoro-1-(trifluoromethoxy)benzene(64.5 g, 249 mmol) in THF (60 mL) was added dropwise over 1 hour. Thesolution was stirred for 1 hour at −70° C. The solution was poured intoa slurry of solid carbon dioxide (dry ice) (150 g, 3.408 mol) in THF(100 mL) and the solution was slowly warmed to room temperature over 1hour, then stirred at room temperature for 2 days. The mixture wasdiluted with MTBE (200 mL) and 2 M aqueous HCl (150 mL). The phases wereseparated and the acidic layer was extracted with additional MTBE (100mL). The combined MTBE layers were extracted with 2 M aqueous NaOH (3×).The combined aqueous extracts were acidified with 2 M aqueous HCl (150mL) until the pH is 1 and extracted with MTBE (3×200 mL). The combinedorganic extracts were dried over Na₂SO₄, filtered and concentrated to anoil. The oil was treated with seed crystals (100 mg) and stirred for 1hour. The suspension was diluted with heptane (65 mL) and filtered. Thesolid was washed with heptane and air dried to provide 58.2 g ofproduct. The filtrate was concentrated in vacuo and another crop ofproduct obtained in a similar fashion to obtain 4.6 g of product. Thetwo crops of solid were combined to provide6-bromo-2-fluoro-3-(trifluoromethoxy)benzoic acid (58.2 g, 77%). ¹H NMR(400 MHz, CDCl₃) δ 11.62 (s, 1H), 7.51 (dd, J=8.8, 1.8 Hz, 1H),7.41-7.30 (m, 1H) ppm.

Step 2:2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethoxy)benzoicacid

A mixture of 6-bromo-2-fluoro-3-(trifluoromethoxy)benzoic acid (500 mg,1.65 mmol), 2-methoxy-4-(trifluoromethoxy)phenol (330 mg, 1.59 mmol) andCs₂CO₃ (575 mg, 1.77 mmol) toluene (20 mL) was bubbled with nitrogen for10 minutes, then treated with copper (I) iodide (112 mg, 0.588 mmol).The mixture was heated at 100° C. with vigorous stirring overnight. Themixture was acidified with 2 M aqueous HCl and the aqueous layer wasextracted with ethyl acetate. The combined organic layers were washedwith brine, dried over MgSO₄, filtered and concentrated to provide2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethoxy)benzoicacid (700 mg, 99%). ESI-MS m z calc. 430.03, no ionization observed;LC/MS retention time (Method F): 0.63 minutes. ¹H NMR (400 MHz, CDCl₃) δ10.01-9.93 (m, 2H), 7.21-7.12 (m, 1H), 7.06-7.00 (m, 1H), 6.76 (dtd,J=9.4, 2.5, 1.4 Hz, 2H), 6.40 (dd, J=9.3, 1.8 Hz, 1H), 3.71 (s, 3H) ppm.

Step 3:4-[[2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethoxy)benzoyl]amino]pyridine-2-carboxamide(280)

To a solution of2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethoxy)benzoicacid (167 mg, 0.388 mmol) and DMF (3 μL, 0.04 mmol) in dichloromethane(4 mL) at 0° C. was added oxalyl chloride (100 μL, 1.15 mmol) dropwiseand the solution stirred for 2 hours. The mixture was concentrated invacuo to afford the acid chloride. The residue was redissolved indichloromethane (4 mL) and added dropwise to a mixture of methyl4-aminopyridine-2-carboxylate (85 mg, 0.56 mmol) and TEA (325 μL, 2.33mmol) in dichloromethane (4 mL) at 0° C. The resulting mixture wasallowed to warm to room temperature and stirred overnight. The mixturewas concentrated in vacuo to provide the intermediate methyl4-[[2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethoxy)benzoyl]amino]pyridine-2-carboxylate.The residue was dissolved in a solution of ammonia in methanol (7 M) inmethanol and stirred overnight. The mixture was concentrated in vacuoand purified by reverse phase HPLC (47-95% acetonitrile/0.1% ammoniumhydroxide) to provide4-[[2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethoxy)benzoyl]amino]pyridine-2-carboxamide(31.7 mg, 14%). ESI-MS m z calc. 549.08, found 550.1 (M+1)⁺; 548.1(M−1)⁻; LC/MS retention time (Method F): 0.94 minutes. ¹H NMR (400 MHz,CDCl₃) δ 9.28 (s, 1H), 8.56 (d, J=5.5 Hz, 1H), 8.46 (dd, J=5.7, 2.1 Hz,1H), 7.98-7.89 (m, 2H), 7.36-7.26 (m, 1H), 7.27-7.17 (m, 1H), 6.96-6.87(m, 2H), 6.57 (dd, J=9.2, 1.8 Hz, 1H), 5.47 (d, J=4.5 Hz, 1H), 3.91 (s,3H) ppm.

Example 914-[[2-cyclopropyl-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(281)

Step 1:2-cyclopropyl-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoicacid

A solution of2-bromo-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoicacid (313 mg, 0.659 mmol, see Example 40) in DMSO (3 mL) was treatedwith cyclopropylboronic acid (85 mg, 0.99 mmol) and aqueous K₂CO₃ (1 mLof 2 M, 2 mmol). Pd(dppf)Cl₂-dichloromethane (27 mg, 0.033 mmol) wasadded and the mixture stirred under nitrogen at 60° C. for 1 hour. Themixture was diluted with ethyl acetate (75 mL) and washed with water(2×75 mL) and brine (75 mL). The organic layer was dried over Na₂SO₄,filtered and concentrated in vacuo. Reverse phase HPLC purification(10-99% acetonitrile/5 mM HCl) provided2-cyclopropyl-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoicacid (53 mg, 18%) as a white solid. ESI-MS m z calc. 436.08, found 437.1(M+1)⁺; LC/MS retention time (Method B): 2.27 minutes.

Step 2:4-[[2-cyclopropyl-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(281)

A solution of2-cyclopropyl-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoicacid (25 mg, 0.057 mmol) and DMF (1 μL, 0.01 mmol) in dichloromethane (2mL) was treated dropwise with oxalyl chloride (30 μL, 0.34 mmol). Themixture was allowed to stir at room temperature for 1 hour and thenconcentrated in vacuo. The acid chloride intermediate was redissolved inNMP (0.5 mL) and added to a mixture of 4-aminopyridine-2-carboxamide (12mg, 0.088 mmol) and DIEA (50 μL, 0.29 mmol). This mixture was stirred at75° C. overnight, then cooled and purified by reverse phase HPLC (1-99%acetonitrile/5 mM HCl) to provide4-[[2-cyclopropyl-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(4.5 mg, 14%) as a white solid. ESI-MS m z calc. 555.12, found 556.2(M+1)⁺; LC/MS retention time (Method B): 1.88 minutes. ¹H NMR (400 MHz,DMSO-d₆) δ 11.20 (s, 1H), 8.54 (d, J=5.5 Hz, 1H), 8.38 (d, J=2.0 Hz,1H), 8.13 (s, 1H), 7.92-7.85 (m, 1H), 7.72 (d, J=9.0 Hz, 1H), 7.68 (s,1H), 7.28 (d, J=8.8 Hz, 1H), 7.23 (d, J=2.7 Hz, 1H), 7.05-6.99 (m, 1H),6.67 (d, J=8.8 Hz, 1H), 3.78 (s, 3H), 2.13 (d, J=8.0 Hz, 1H), 0.88 (dd,J=8.6, 4.6 Hz, 2H), 0.77 (d, J=6.2 Hz, 2H) ppm.

Example 92N-(2-carbamoyl-4-pyridyl)-5-cyclopropyl-3-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-(trifluoromethyl)pyridine-2-carboxamide(282)

Step 1: 3-bromo-5-fluoro-2-iodo-pyridine

A mixture of 2,3-dibromo-5-fluoro-pyridine (10.54 g, 41.35 mmol), sodiumiodide (6.1 g, 41 mmol), copper (I) iodide (390 mg, 2.05 mmol) andN,N-dimethylethylenediamine (363 mg, 0.45 mL, 4.12 mmol) in dioxane (60mL) was stirred overnight at 100° C. under nitrogen atmosphere. Themixture was cooled to room temperature, diluted with ethyl acetate (50mL) and filtered through Celite. The filtrate was concentrated in vacuoand purified by silica gel chromatography (0-20% ethyl acetate/heptane)to give 10.5 g of a white solid. The solid was dissolved in MTBE (50 mL)at 40° C., cooled to room temperature and precipitated by addition ofpentane (50 mL). The resulting solid was filtered to provide3-bromo-5-fluoro-2-iodo-pyridine (3.43 g, 25%) as a white solid. Thefiltrate was concentrated in vacuo to provide additional3-bromo-5-fluoro-2-iodo-pyridine (6.95 g, 48%) as a white solid. ¹H NMR(300 MHz, CDCl₃) δ 8.27 (d, J=2.6 Hz, 1H), 7.63 (dd, J=7.6, 2.6 Hz, 1H)ppm. ¹⁹F NMR (282 MHz, CDCl₃) δ −126.32-−126.45 (m, 1F) ppm.

Step 2: 3-bromo-5-fluoro-2-(trifluoromethyl)pyridine

A mixture of potassium fluoride (360 mg, 6.20 mmol) and copper (I)iodide (1.15 g, 6.04 mmol) were heated under vacuum with gentle shakinguntil a yellow/greenish color was obtained. Once back to roomtemperature, nitrogen-degassed NMP (17 mL) andtrimethyl(trifluoromethyl)silane (847 mg, 0.88 mL, 5.95 mmol) were addedto the solid. The resulting mixture was stirred at 50° C. for 45minutes, then 3-bromo-5-fluoro-2-iodo-pyridine (1.0 g, 2.8 mmol) wasadded. The mixture was stirred at 80° C. for 3 hours. The stirringmixture was cooled to room temperature and diluted with diethyl ether(150 mL) and aqueous NH₄OH (150 mL, 9% solution). The aqueous layer wasseparated and extracted with additional diethyl ether (60 mL). Thecombined organic layers were washed with aqueous NH₄OH (3×50 mL, 9%solution), water (50 mL) and brine (100 mL). The solution was dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo to provide3-bromo-5-fluoro-2-(trifluoromethyl)pyridine (641 mg, 85%). ¹H NMR (300MHz, CDCl₃) δ 8.53-8.45 (m, 1H), 7.88-7.79 (m, 1H) ppm. ¹⁹F NMR (282MHz, CDCl₃) δ −65.44 (s, 3F), −118.93 (d, J=6.1 Hz, 1F) ppm.

Step 3:3-bromo-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine

A vial of 3-bromo-5-fluoro-2-(trifluoromethyl)pyridine (1.0 g, 4.1mmol), 2-methoxy-4-(trifluoromethoxy)phenol (853 mg, 4.10 mmol) andCs₂CO₃ (1.48 g, 4.55 mmol) was flushed with nitrogen and DMF (33 mL) wasadded. The mixture was heated at 100° C. for 1 hour, then diluted withethyl acetate and washed with water. The organic layer was dried andconcentrated in vacuo to provide3-bromo-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine(1.83 g, 97%). ESI-MS m z calc. 430.96, found 432.4 (M+1)⁺; LC/MSretention time (Method F): 1.09 minutes. ¹H NMR (500 MHz, CDCl₃) δ 8.19(d, J=2.4 Hz, 1H), 7.34 (dd, J=2.5, 0.6 Hz, 1H), 7.08 (d, J=9.4 Hz, 1H),6.89-6.77 (m, 2H), 3.74 (s, 3H) ppm.

Step 4:3-cyclopropyl-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine

A mixture of3-bromo-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine(1.871 g, 3.897 mmol), cyclopropylboronic acid (1.103 g, 12.84 mmol),Pd(OAc)₂ (200 mg, 0.891 mmol), tricyclohexylphosphine (120 mg, 0.428mmol) and K₃PO₄ (2.87 g, 13.5 mmol) in toluene (30 mL) and water (7.5mL) was purged with nitrogen and heated at 100° C. for 2 hours. Themixture was diluted with ethyl acetate and washed with water (3×). Theorganic layer was dried over MgSO₄, filtered and concentrated in vacuo.Purification by silica gel chromatography (0-20% ethyl acetate/heptane)provided3-cyclopropyl-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine(1.413 g, 92%). ESI-MS m z calc. 393.08, found 394.6 (M+1)⁺; LC/MSretention time (Method F): 1.09 minutes. ¹H NMR (500 MHz, CDCl₃) δ 7.95(d, J=2.6 Hz, 1H), 7.00 (dd, J=8.4, 0.6 Hz, 1H), 6.85-6.73 (m, 3H), 3.73(s, 3H), 2.15 (dddd, J=12.0, 8.5, 4.3, 1.7 Hz, 1H), 1.09-0.91 (m, 2H),0.62 (dt, J=6.7, 5.0 Hz, 2H) ppm.

Step 5:3-cyclopropyl-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]-1-oxido-2-(trifluoromethyl)pyridin-1-ium

To a solution of3-cyclopropyl-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine(1.305 g, 3.318 mmol) in dichloromethane (25 mL) at 0° C. was addedhydrogen peroxide urea (1.116 g, 11.86 mmol) followed by the dropwiseaddition of trifluoroacetic anhydride (2.56 g, 1.69 mL, 12.2 mmol). Themixture was warmed to room temperature and stirred for 20 hours. Themixture was diluted with ethyl acetate and washed with water. Theaqueous layer was extracted with additional ethyl acetate, and thecombined organic extracts dried and concentrated in vacuo. Purificationby silica gel chromatography (0-20% ethyl acetate/heptane) provided3-cyclopropyl-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]-1-oxido-2-(trifluoromethyl)pyridin-1-ium(915 mg, 58%). ESI-MS m z calc. 409.08, found 410.5 (M+1)⁺; 408.6(M−1)⁻; LC/MS retention time (Method F): 0.94 minutes.

Step 6:2-bromo-5-cyclopropyl-3-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-(trifluoromethyl)pyridine

To a solution of3-cyclopropyl-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]-1-oxido-2-(trifluoromethyl)pyridin-1-ium(1.0 g, 2.1 mmol) in toluene (25 mL) was added POBr₃ (611 mg, 2.131mmol). The mixture was heated at 100° C. for 2 hours, and then cooledand partitioned between ethyl acetate and water. The layers wereseparated and the aqueous layer extracted with additional ethyl acetate.The combined organic extracts were dried over MgSO₄, filtered andconcentrated in vacuo. The residue was purified by silica gelchromatography (0-10% ethyl acetate/heptane) to provide2-bromo-5-cyclopropyl-3-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-(trifluoromethyl)pyridine(782 mg, 79%). ESI-MS m z calc. 471.00, found 474.4 (M+1)⁺; LC/MSretention time (Method F): 1.14 minutes. ¹H NMR (500 MHz, CDCl₃) δ7.12-7.04 (m, 1H), 6.93-6.83 (m, 2H), 6.46 (s, 1H), 3.80 (s, 3H), 2.14(td, J=6.4, 5.8, 2.8 Hz, 1H), 1.10-0.99 (m, 2H), 0.52 (dt, J=6.6, 5.0Hz, 2H) ppm.

Step 7:5-cyclopropyl-3-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-(trifluoromethyl)pyridine-2-carbonitrile

A solution of2-bromo-5-cyclopropyl-3-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-(trifluoromethyl)pyridine(500 mg, 1.06 mmol), Zn(CN)₂ (113 mg, 0.962 mmol), Pd(dppf)Cl₂ (57 mg,0.077 mmol), Pd₂dba₃ (53 mg, 0.058 mmol) and zinc (32 mg, 0.49 mmol) inDMF (10 mL) was heated at 100° C. for 20 hours. Additional Zn(CN)₂ (75mg, 0.64 mmol) was added and the mixture heated at 100° C. for 1 hour.Additional Pd(dppf)Cl₂ (42 mg, 0.058 mmol) and Pd₂dba₃ (41 mg, 0.045mmol) was then added and heating continued at 100° C. for 1 hour. Themixture was cooled, diluted with saturated aqueous NaHCO₃ and extractedwith ethyl acetate. The organic layer was washed with water (3×), driedover MgSO₄, filtered and concentrated in vacuo. The residue was purifiedby silica gel chromatography (0-10% ethyl acetate/heptane) to provide5-cyclopropyl-3-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-(trifluoromethyl)pyridine-2-carbonitrile(257 mg, 45%). ESI-MS m z calc. 418.08, found 419.6 (M+1)⁺; LC/MSretention time (Method F): 1.07 minutes.

Step 8:5-cyclopropyl-3-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-(trifluoromethyl)pyridine-2-carboxylicacid

To a solution of5-cyclopropyl-3-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-(trifluoromethyl)pyridine-2-carbonitrile(91 mg, 0.17 mmol) in ethanol (750 μL) was added aqueous NaOH (500 μL of5 M, 2.5 mmol). The mixture was heated at 80° C. for 30 minutes, andthen was diluted with water and extracted with ethyl acetate. Theorganic extract was dried over MgSO₄, filtered and concentrated in vacuoto provide5-cyclopropyl-3-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-(trifluoromethyl)pyridine-2-carboxylicacid (69 mg, 81%). ESI-MS m z calc. 437.07, found 438.5 (M+1)⁺; 436.7(M−1)⁻; LC/MS retention time (Method F): 0.64 minutes.

Step 9:N-(2-carbamoyl-4-pyridyl)-5-cyclopropyl-3-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-(trifluoromethyl)pyridine-2-carboxamide(282)

To a solution of5-cyclopropyl-3-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-(trifluoromethyl)pyridine-2-carboxylicacid (13 mg, 0.026 mmol) in dichloromethane (300 μL) and DMF (0.2 μL,0.003 mmol) at 0° C. was added oxalyl chloride (9 μL, 0.1 mmol) and thesolution was warmed to room temperature and stirred for 1 hour. Themixture was concentrated in vacuo, redissolved in dichloromethane (300μL) and added to a solution of methyl 4-aminopyridine-2-carboxylate (4mg, 0.03 mmol) and TEA (10 μL, 0.072 mmol) in dichloromethane (200 μL)at 0° C. The mixture was warmed to room temperature and stirred for 3hours. The mixture was diluted with dichloromethane and washed withwater. The organic layer was dried and concentrated in vacuo. Theresidue was dissolved in a solution of ammonia in methanol (1 mL of 7 M,7 mmol) and stirred at room temperature for 60 hours. The mixture wasconcentrated in vacuo and purified by reverse phase HPLC (47-95%acetonitrile/0.1% ammonium hydroxide) to provideN-(2-carbamoyl-4-pyridyl)-5-cyclopropyl-3-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-(trifluoromethyl)pyridine-2-carboxamide(2 mg, 14%). ESI-MS m z calc. 556.12, found 557.5 (M+1)⁺; 555.6 (M−1)⁻;LC/MS retention time (Method E): 3.45 minutes.

Example 934-[[4-methoxy-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(283)

Step 1: methyl 4-methoxy-2-methyl-3-(trifluoromethyl)benzoate

To a solution of methyl 3-bromo-4-methoxy-2-methyl-benzoate (3.964 g,15.30 mmol) and copper (I) iodide (615 mg, 3.23 mmol) in DMF (38 mL)under nitrogen was added methyl 2,2-difluoro-2-(fluorosulfonyl)acetate(4.2 mL, 33 mmol). The mixture was heated at 120° C. for 3 hours.Additional copper (I) iodide (596 mg, 3.13 mmol) was added and themixture was heated at 120° C. for an additional 30 minutes. Additionalcopper (I) iodide (1.746 g, 9.168 mmol) and methyl2,2-difluoro-2-fluorosulfonyl-acetate (4.2 mL, 33 mmol) were added andthe mixture was then heated at 120° C. for 20 hours. The mixture wasadded to ice-cold saturated aqueous NaHCO₃ (300 mL) and extracted withethyl acetate (2×175 mL). The combined organic extracts were washed withwater (5×100 mL), dried over MgSO₄, filtered and concentrated in vacuo.Two sequential purifications by silica gel chromatography (0-5% ethylacetate/heptane) provided methyl4-methoxy-2-methyl-3-(trifluoromethyl)benzoate (1.114 g, 29%). ESI-MS mz calc. 248.07, found 249.5 (M+1)⁺; LC/MS retention time (Method F):0.87 minutes. ¹H NMR (500 MHz, CDCl₃) δ 7.89 (d, J=8.8 Hz, 1H), 6.87 (d,J=8.8 Hz, 1H), 3.91 (s, 3H), 3.89 (s, 3H), 2.63 (q, J=3.3 Hz, 3H) ppm.

Step 2: 4-methoxy-2-methyl-3-(trifluoromethyl)benzoic acid

To a solution of methyl 4-methoxy-2-methyl-3-(trifluoromethyl)benzoate(317 mg, 1.28 mmol) in THF (12 mL) and methanol (4 mL) at 0° C. wasadded aqueous NaOH (9 mL of 2 M, 18.00 mmol). The mixture was stirred atroom temperature for 2 hours and then concentrated to remove organicsolvents. The remaining aqueous solution was diluted with water (200 mL)and washed with ethyl acetate (3×100 mL). The aqueous solution wasacidified to pH 3 and extracted with ethyl acetate (3×100 mL). Thecombined organic extracts were washed with water (2×75 mL), dried overMgSO₄, filtered and concentrated in vacuo to provide4-methoxy-2-methyl-3-(trifluoromethyl)benzoic acid (285 mg, 95%). ESI-MSm z calc. 234.05, found 233.6 (M−1)⁻; LC/MS retention time (Method F):0.4 minutes. ¹H NMR (500 MHz, DMSO-d₆) δ 13.02 (s, 1H), 7.93 (d, J=8.8Hz, 1H), 7.18 (d, J=8.8 Hz, 1H), 3.90 (s, 3H), 2.56 (q, J=3.4 Hz, 3H)ppm.

Step 3: 6-iodo-4-methoxy-2-methyl-3-(trifluoromethyl)benzoic acid

A mixture of 4-methoxy-2-methyl-3-(trifluoromethyl)benzoic acid (475 mg,2.03 mmol), N-iodosuccinimide (502 mg, 2.23 mmol) and Pd(OAc)₂ (45 mg,0.20 mmol) in DMF (10 mL) was heated under nitrogen at 100° C. for 90minutes. The mixture was diluted with ethyl acetate (25 mL) and washedwith water (5×20 mL) and brine (20 mL). The organic phase was dried overMgSO₄, filtered and concentrated in vacuo to provide6-iodo-4-methoxy-2-methyl-3-(trifluoromethyl)benzoic acid (360 mg, 28%,contaminated with unreacted starting material). ESI-MS m z calc. 359.95,found 359.5 (M−1)⁻; LC/MS retention time (Method F): 0.41 minutes. Thematerial was used without additional purification.

Step 4:4-methoxy-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-3-(trifluoromethyl)benzoicacid

A solution of 6-iodo-4-methoxy-2-methyl-3-(trifluoromethyl)benzoic acid(360 mg, 0.640 mmol), 2-methoxy-4-(trifluoromethoxy)phenol (216 mg, 1.04mmol) and Cs₂CO₃ (524 mg, 1.61 mmol) in toluene (8 mL) was flushed withnitrogen for 10 minutes. Copper (I) iodide (34 mg, 0.18 mmol) was addedand the mixture heated at 100° C. for 16 hours under nitrogen. Themixture was diluted with water (100 mL) and extracted with ethyl acetate(100 mL). The organic layer was washed with saturated aqueous NaHCO₃ (75mL), 1 M aqueous NaOH (75 mL×3) and brine (30 mL). The organic layer wasdried over MgSO₄, filtered and concentrated in vacuo to provide4-methoxy-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-3-(trifluoromethyl)benzoicacid (183 mg, 53%). ESI-MS m z calc. 440.07, found 441.5 (M+1)⁺; 439.6(M−1)⁻; LC/MS retention time (Method F): 0.62 minutes.

Step 5: methyl4-[[4-methoxy-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxylate

To a solution of4-methoxy-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-3-(trifluoromethyl)benzoicacid (188 mg, 0.350 mmol) and DMF (3 μL, 0.04 mmol) in dichloromethane(3 mL) at 0° C. was added oxalyl chloride (100 μL, 1.15 mmol). Themixture was warmed to room temperature and stirred for 20 minutes. Themixture was concentrated in vacuo, then redissolved in dichloromethane(2 mL) and added dropwise to a solution of methyl4-aminopyridine-2-carboxylate (52.8 mg, 0.347 mmol) and TEA (150 μL,1.08 mmol) in dichloromethane (2 mL) at 0° C. The mixture was allowed towarm to room temperature and stirred for 20 hours. The mixture wasdiluted with dichloromethane (20 mL) and washed with water (20 mL). Theaqueous layer was extracted with additional dichloromethane (2×20 mL),and then the combined organic extracts dried over MgSO₄, filtered andconcentrated in vacuo. Purification by column chromatography (0-60%ethyl acetate/heptane) provided methyl4-[[4-methoxy-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxylate(43 mg, 21%). ESI-MS m z calc. 574.12, found 575.5 (M+1)⁺; 573.6 (M−1)⁻;LC/MS retention time (Method F): 0.98 minutes. ¹H NMR (500 MHz, DMSO-d₆)δ 11.14 (s, 1H), 8.59 (d, J=5.5 Hz, 1H), 8.40 (d, J=2.0 Hz, 1H), 7.81(dd, J=5.4, 2.2 Hz, 1H), 7.23 (d, J=8.8 Hz, 1H), 7.18 (d, J=2.8 Hz, 1H),6.98 (d, J=8.6 Hz, 1H), 6.36 (s, 1H), 3.87 (s, 3H), 3.77 (s, 3H), 3.70(s, 3H), 2.38 (q, J=3.3 Hz, 3H) ppm.

Step 6:4-[[4-methoxy-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(283)

Methyl4-[[4-methoxy-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxylate(40 mg, 0.070 mmol) was dissolved in a solution of ammonia in methanol(1 mL of 7 M, 7 mmol) and stirred at room temperature for 24 hours. Themixture was concentrated in vacuo and partitioned betweendichloromethane and water. The layers were separated, and the aqueouslayer extracted with additional dichloromethane (2×20 mL). The combinedorganic extracts were dried over MgSO₄, filtered and concentrated invacuo to provide4-[[4-methoxy-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(20 mg, 49%). ESI-MS m z calc. 559.12, found 560.3 (M+1)⁺; 558.4 (M−1)⁻;LC/MS retention time (Method E): 3.31 minutes. ¹H NMR (500 MHz, DMSO-d₆)δ 11.09 (s, 1H), 8.51 (d, J=5.6 Hz, 1H), 8.32 (d, J=2.1 Hz, 1H), 8.06(d, J=2.9 Hz, 1H), 7.82 (dd, J=5.5, 2.2 Hz, 1H), 7.61 (d, J=2.9 Hz, 1H),7.25 (d, J=8.8 Hz, 1H), 7.18 (d, J=2.8 Hz, 1H), 6.99 (ddd, J=8.8, 2.8,1.3 Hz, 1H), 6.34 (s, 1H), 3.78 (s, 3H), 3.70 (s, 3H), 2.39 (q, J=3.3Hz, 3H) ppm.

Example 944-[[2-fluoro-3-methoxy-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(284)

Step 1: 1-fluoro-2-methoxy-3-(trifluoromethyl)benzene

A solution of 1,2-difluoro-3-(trifluoromethyl)benzene (101.2 g, 555.8mmol) in MTBE (800 mL) was treated with a solution of sodium methoxide(180 mL of 25% w/v, 833 mmol) at room temperature, with a slightendotherm observed. The mixture was heated at 43° C. for 30 hours, andthen treated with additional sodium methoxide solution (40 mL of 25%w/v, 185.1 mmol) and heated at 50° C. overnight. The mixture was cooledto room temperature, diluted with water (830 mL) and the biphasicmixture filtered. The aqueous phase was separated and extracted withadditional MTBE (2×300 mL). The combined organic layers were dried overMgSO₄, filtered and concentrated in vacuo to provide1-fluoro-2-methoxy-3-(trifluoromethyl)benzene (103.9 g, 90%) as acolorless oil. ¹H NMR (400 MHz, DMSO-d₆) δ 7.69-7.59 (m, 1H), 7.49 (ddq,J=7.9, 1.4, 0.7 Hz, 1H), 7.35-7.24 (m, 1H), 3.95 (d, J=2.0 Hz, 3H) ppm.

Step 2: 2-fluoro-3-methoxy-4-(trifluoromethyl)benzoic acid

A solution of diisopropylamine (80 mL, 571 mmol) in THF (620 mL) wascooled to −20° C. and treated with n-butyllithium (225 mL of 2.5 M inhexane, 562.5 mmol) at a rate to maintain the internal temperature below−15° C. After complete addition, the cooling bath was removed and themixture was allowed to warm to 0° C. The mixture was then cooled to −74°C. and treated with a solution of1-fluoro-2-methoxy-3-(trifluoromethyl)benzene (103.9 g, 498.7 mmol) inTHF (210 mL) over 25 minutes while maintaining the internal temperaturebelow −69° C. The mixture was stirred for an additional 30 minutes at−74° C., then poured into a slurry of excess solid carbon dioxide (dryice) in THF (320 mL). The mixture was stirred until room temperature hadbeen reached and no more effervescence was observed. The mixture waspartitioned between 2 M aqueous NaOH (500 mL) and MTBE (130 mL), andthen further diluted with water (450 mL). The aqueous phase wasseparated and washed with additional MTBE (130 mL). The aqueous phasewas then acidified with 2 M aqueous HCl and extracted with MTBE (2×250mL). The combined organic extracts were dried over MgSO₄, filtered andconcentrated in vacuo to provide2-fluoro-3-methoxy-4-(trifluoromethyl)benzoic acid (110 g, 93%) as awhite solid. ESI-MS m z calc. 238.03, found 237.0 (M−1)⁻; LC/MSretention time (Method F): 0.46 minutes. ¹H NMR (400 MHz, DMSO-d₆) δ13.80 (s, 1H), 7.75-7.64 (m, 1H), 7.57 (dd, J=8.4, 1.4 Hz, 1H), 3.97 (d,J=1.8 Hz, 3H) ppm.

Step 3: 2-fluoro-6-iodo-3-methoxy-4-(trifluoromethyl)benzoic acid

A solution of 2-fluoro-3-methoxy-4-(trifluoromethyl)benzoic acid (497mg, 2.09 mmol) in trifluoroacetic acid (1 mL) and sulfuric acid (300 μL)was treated with N-iodosuccinimide (800 mg, 3.56 mmol) in one portionand stirred at room temperature for 3 hours. The mixture was dilutedwith dichloromethane and water (exothermic). The phases were separatedand the aqueous layer was extracted with additional dichloromethane. Thecombined organic phases were washed with saturated aqueous Na₂S₂O₃,dried over MgSO₄, filtered and concentrated in vacuo. Purification usingsilica gel chromatography (0-100% ethyl acetate/heptane) provided2-fluoro-6-iodo-3-methoxy-4-(trifluoromethyl)benzoic acid (708 mg, 93%).ESI-MS m z calc. 363.92, no ionization observed; LC/MS retention time(Method F): 0.45 minutes. ¹H NMR (400 MHz, CDCl₃) δ 7.86 (dd, J=1.7, 0.7Hz, 1H), 4.07 (d, J=2.4 Hz, 3H), 2.85 (s, 1H) ppm.

Step 4:2-fluoro-3-methoxy-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoicacid

A mixture of 2-fluoro-6-iodo-3-methoxy-4-(trifluoromethyl)benzoic acid(300 mg, 0.618 mmol), 2-methoxy-4-(trifluoromethoxy)phenol (257 mg, 1.24mmol) and Cs₂CO₃ (537 mg, 1.65 mmol) in toluene (11 mL) was bubbled withnitrogen for 10 minutes, then copper (I) iodide (31.39 mg, 0.1648 mmol)added. The mixture was heated at 100° C. under nitrogen with vigorousstirring for 16 hours. The mixture was allowed to cool and waspartitioned between ethyl acetate and water. The separated aqueous layerwas acidified with aqueous HCl and extracted with ethyl acetate. Theorganic layer was washed with brine, dried over MgSO₄, filtered andconcentrated in vacuo. Purification by silica gel chromatography (0-60%ethyl acetate/heptane) provided2-fluoro-3-methoxy-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoicacid (160 mg, 58%) as a pale orange oil that crystallized on standing.ESI-MS m z calc. 444.04, found 443.4 (M−1)⁻; LC/MS retention time(Method F): 0.62 minutes. ¹H NMR (500 MHz, CDCl₃) δ 7.23-7.06 (m, 1H),6.91 (ddd, J=7.1, 2.3, 1.1 Hz, 2H), 6.73 (d, J=1.8 Hz, 1H), 4.02 (d,J=1.5 Hz, 3H), 3.85 (s, 3H) ppm.

Step 5: methyl4-[[2-fluoro-3-methoxy-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxylate

A solution of2-fluoro-3-methoxy-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoicacid (55 mg, 0.12 mmol) and DMF (0.5 μL, 0.007 mmol) in dichloromethane(3 mL) at 0° C. was treated with oxalyl chloride (2.5 mL, 29 mmol). Themixture was stirred for 1 hour before being concentrated in vacuo. Theresidue was redissolved in dichloromethane (3 mL) and treated with DIPEA(36 μL, 0.21 mmol) and methyl 4-aminopyridine-2-carboxylate (21 mg, 0.14mmol). The mixture was stirred overnight, then concentrated in vacuo andpurified by reverse phase HPLC (47-95% acetonitrile/0.1% ammoniumhydroxide) to provide methyl4-[[2-fluoro-3-methoxy-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxylate(56 mg, 78%). ESI-MS m z calc. 578.09, found 579.5 (M+1)⁺; 577.5 (M−1)⁻;LC/MS retention time (Method F): 0.96 minutes.

Step 6:4-[[2-fluoro-3-methoxy-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(284)

Methyl4-[[2-fluoro-3-methoxy-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxylate(56 mg, 0.10 mmol) was dissolved in a solution of ammonia in methanol(2.8 mL of 7 M, 19.6 mmol) and stirred at room temperature overnight.The mixture was concentrated in vacuo to provide4-[[2-fluoro-3-methoxy-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(40 mg, 71%). ESI-MS m z calc. 563.09, found 564.5 (M+1)⁺; 562.4 (M−1)⁻;LC/MS retention time (Method E): 3.37 minutes. ¹H NMR (500 MHz, CDCl₃) δ9.19 (s, 1H), 8.56 (d, J=5.5 Hz, 1H), 8.41 (dd, J=5.6, 2.2 Hz, 1H), 7.92(d, J=2.2 Hz, 2H), 7.26-7.15 (m, 1H), 7.02-6.86 (m, 2H), 6.76 (d, J=1.9Hz, 1H), 5.57 (d, J=4.5 Hz, 1H), 4.03 (d, J=1.5 Hz, 3H), 3.93 (s, 3H)ppm.

Example 954-[[2-fluoro-6-[2-methyl-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]-5-methyl-pyridine-2-carboxamide(285)

To a solution of2-fluoro-6-[2-methyl-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoicacid (300 mg, 0.753 mmol, see US 2019/0016671, Example 10, Step 1, whichis incorporated by reference) and DMF (6 μL, 0.08 mmol) indichloromethane (7 mL) at 0° C. was added oxalyl chloride (190 μL, 2.25mmol) dropwise. The mixture was stirred for 2 hours, and thenconcentrated in vacuo. The residue was redissolved in dichloromethane (7mL) and added dropwise to a mixture of methyl4-amino-5-methyl-pyridine-2-carboxylate (175 mg, 1.053 mmol,Preparation 1) and TEA (630 μL, 4.520 mmol) in dichloromethane (7 mL) at0° C. The resulting mixture allowed to warm to room temperature andstirred overnight. The mixture was concentrated in vacuo and purified byreverse phase HPLC (47-95% acetonitrile/0.1% ammonium hydroxide) toprovide4-[[2-fluoro-6-[2-methyl-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]-5-methyl-pyridine-2-carboxamide(66 mg, 16%). ESI-MS m z calc. 531.10, found 532.1 (M+1)⁺; 530.2 (M−1)⁻;LC/MS retention time (Method F): 0.95 minutes. ¹H NMR (400 MHz, DMSO-d₆)δ 10.65 (s, 1H), 8.48 (s, 2H), 8.06 (d, J=2.5 Hz, 1H), 7.84 (t, J=8.7Hz, 1H), 7.61 (d, J=2.7 Hz, 1H), 7.45 (dd, J=2.7, 1.6 Hz, 1H), 7.38-7.24(m, 2H), 6.71 (d, J=8.9 Hz, 1H), 2.31 (s, 3H), 2.22 (s, 3H) ppm.

Example 964-[[3-chloro-2-fluoro-6-[2-methyl-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(286)

Step 1: 6-bromo-3-chloro-2-fluoro-benzoic acid

A solution of diisopropylamine (94 mL, 671 mmol) in THF (840 mL) wascooled to −20° C. A solution of n-butyllithium (264 mL of 2.5 M inhexanes, 660 mmol) was added at such a rate to keep the internaltemperature below −15° C. After complete addition, the cooling bath wasremoved and the mixture allowed to warm to 0° C. The mixture then wascooled to −74° C. and treated with a solution of4-bromo-1-chloro-2-fluoro-benzene (120.2 g, 573.9 mmol) in THF (200 mL)over 30 minutes while maintaining the internal temperature below −70° C.The mixture was stirred for an additional 30 minutes at −74° C., thenpoured into a slurry of excess solid carbon dioxide (dry ice) in THF(320 mL). The mixture was stirred until room temperature had beenreached and no more effervescence was observed. The mixture waspartitioned between 2 M aqueous NaOH (600 mL) and MTBE (200 mL), andthen further diluted with water (240 mL). The aqueous phase wasseparated and washed with additional MTBE (200 mL). The aqueous phasewas then acidified with 2 M aqueous HCl and extracted with MTBE (2×400mL). The combined organic extracts were dried over MgSO₄, filtered andconcentrated in vacuo to provide 6-bromo-3-chloro-2-fluoro-benzoic acid(135.4 g, 93%). ¹H NMR (400 MHz, DMSO-d₆) δ 14.38 (s, 1H), 7.95-7.23 (m,2H) ppm.

Step 2:3-chloro-2-fluoro-6-[2-methyl-4-(trifluoromethoxy)phenoxy]benzoic acid

A mixture of 6-bromo-3-chloro-2-fluoro-benzoic acid (800 mg, 3.16 mmol),2-methyl-4-(trifluoromethoxy)phenol (800 mg, 3.54 mmol) and Cs₂CO₃ (2.0g, 6.1 mmol) in toluene (12 mL) was heated at 100° C. and then treatedwith copper (I) iodide (120 mg, 0.630 mmol). The mixture was heated at100° C. overnight, then cooled and diluted with water and ethyl acetate.The aqueous layer was acidified with 2 M aqueous HCl and the layersseparated. The organic layer was washed with water, dried over Na₂SO₄,filtered and concentrated in vacuo to provide3-chloro-2-fluoro-6-[2-methyl-4-(trifluoromethoxy)phenoxy]benzoic acid(1.3 g, 90%). ¹H NMR (400 MHz, DMSO-d₆) δ 14.05 (s, 2H), 9.65 (s, 1H),7.40 (d, J=2.9 Hz, 1H), 7.24 (dd, J=8.9, 2.9 Hz, 1H), 7.07 (d, J=3.2 Hz,1H), 6.98 (dd, J=8.7, 3.0 Hz, 1H), 6.82 (d, J=8.7 Hz, 1H), 6.69 (dd,J=9.0, 1.5 Hz, 1H) ppm.

Step 3:4-[[3-chloro-2-fluoro-6-[2-methyl-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(286)

A solution of3-chloro-2-fluoro-6-[2-methyl-4-(trifluoromethoxy)phenoxy]benzoic acid(260 mg, 0.570 mmol) and DMF (45 μL, 0.58 mmol) in dichloromethane (3mL) at 0° C. was treated with oxalyl chloride (200 μL, 2.29 mmol). Themixture was stirred for 1 hour, and then concentrated in vacuo. Theresidue was redissolved in dichloromethane (3 mL) and added dropwise toa stirring solution of methyl 4-aminopyridine-2-carboxylate (100 mg,0.624 mmol), DIPEA (303 μL, 1.74 mmol) and DMAP (70 mg, 0.57 mmol) indichloromethane (3 mL). The mixture was stirred overnight thenconcentrated in vacuo. The residue was dissolved in a solution ofammonia in methanol (7 M) and stirred overnight. The mixture wasconcentrated and purified by reverse phase HPLC (47-95%acetonitrile/0.1% ammonium hydroxide) to provide4-[[3-chloro-2-fluoro-6-[2-methyl-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(13.9 mg, 5%). ESI-MS m z calc. 483.06, found 484.1 (M+1)⁺; 482.1(M−1)⁻; LC/MS retention time (Method F): 0.91 minutes. ¹H NMR (400 MHz,CDCl₃) δ 9.66 (s, 1H), 8.58-8.47 (m, 2H), 8.20 (d, J=2.1 Hz, 1H), 7.93(s, 1H), 7.43 (dd, J=9.0, 8.0 Hz, 1H), 7.14-7.00 (m, 3H), 6.54 (dd,J=8.9, 1.4 Hz, 1H), 5.16 (s, 1H), 2.22 (s, 3H) ppm.

Example 975-[[6-[2-chloro-4-(trifluoromethoxy)phenoxy]-3-cyclopropyl-2-methyl-benzoyl]amino]pyridine-2-carboxamide(287)

A solution of6-[2-chloro-4-(trifluoromethoxy)phenoxy]-3-cyclopropyl-2-methyl-benzoylchloride (40 mg, 0.10 mmol, see Example 42, Step 5) in NMP (0.3 mL) wasadded to a mixture of 5-aminopyridine-2-carboxamide (20.3 mg, 0.148mmol) and DIEA (69 μL, 0.40 mmol) in NMP (0.3 mL). The mixture wasstirred at room temperature for 16 hours. HATU (75 mg, 0.20 mmol) andDIEA (69 μL, 0.40 mmol) were added and the mixture stirred at 60° C. for16 hours. The mixture was filtered and purified by reverse phase HPLC(30-99% acetonitrile/5 mM HCl) to provide5-[[6-[2-chloro-4-(trifluoromethoxy)phenoxy]-3-cyclopropyl-2-methyl-benzoyl]amino]pyridine-2-carboxamide(6.4 mg, 13%). ESI-MS m z calc. 505.10, found 506.0 (M+1)⁺; LC/MSretention time (Method B): 1.91 minutes. ¹H NMR (400 MHz, DMSO-d₆) δ11.00 (s, 1H), 8.82 (s, 1H), 8.25 (d, J=10.4 Hz, 1H), 8.01 (d, J=8.8 Hz,2H), 7.65 (s, 1H), 7.53 (s, 1H), 7.37 (d, J=10.4 Hz, 1H), 7.13 (d, J=8.7Hz, 2H), 6.77 (d, J=8.5 Hz, 1H), 2.41 (s, 3H), 1.95 (s, 1H), 0.96 (d,J=8.3 Hz, 2H), 0.62 (d, J=5.0 Hz, 2H) ppm.

Example 984-[[6-[3-fluoro-2-methyl-4-(trifluoromethoxy)phenoxy]-2-methyl-3-(trifluoromethyl)benzoyl]amino]-5-methyl-pyridine-2-carboxamide(288)

Step 1: 1-bromo-3-fluoro-2-methyl-4-(trifluoromethoxy)benzene

n-Butyllithium (14.5 mL of 1.6 M in hexanes, 23.2 mmol) was added to astirring solution of diisopropylamine (3.0 mL, 21.4 mmol) in THF (50 mL)at −78° C. The mixture stirred for 20 minutes, then treated dropwisewith 4-bromo-2-fluoro-1-(trifluoromethoxy)benzene (5.0 g, 19.3 mmol).The mixture was stirred at −78° C. for 20 minutes then treated withiodomethane (1.85 mL, 29.7 mmol). The mixture was stirred at −78° C. foran additional 30 minutes then allowed to warm to room temperatureovernight. The mixture was diluted with aqueous NH₄Cl (50 mL) and waterand extracted with ethyl acetate (2×50 mL). The combined organic layerswere concentrated in vacuo to provide1-bromo-3-fluoro-2-methyl-4-(trifluoromethoxy)benzene (4.7 g, 89%). ¹HNMR (400 MHz, CDCl₃) δ 7.28 (dd, J=8.9, 2.0 Hz, 1H), 6.96 (dddt, J=9.0,7.7, 1.3, 0.7 Hz, 1H), 2.30 (d, J=2.7 Hz, 3H) ppm.

Step 2: 3-fluoro-2-methyl-4-(trifluoromethoxy)phenol

To a solution of 1-bromo-3-fluoro-2-methyl-4-(trifluoromethoxy)benzene(2.184 g, 7.999 mmol) in dioxane (11.4 mL) and water (7 mL) was addedsolid KOH (2.3 g, 41 mmol). The resulting solution was stirred for 15minutes (until solids were dissolved). Pd(dba)₂ (115 mg, 0.200 mmol) andtBuXPhos (85 mg, 0.20 mmol) were added and the resulting solution washeated at 90° C. for 12 hours. The mixture was cooled to roomtemperature, partitioned between water and MTBE, and the biphasicmixture filtered. The layers were separated and the organic phase wasconcentrated in vacuo. The resulting oil was purified by silica gelchromatography (ethyl acetate/heptane gradient) to provide3-fluoro-2-methyl-4-(trifluoromethoxy)phenol (1.57 g, 93%). ESI-MS m zcalc. 210.03, found 209.3 (M−1)⁻; LC/MS retention time (Method E): 1.99minutes. ¹H NMR (400 MHz, CDCl₃) δ 7.02 (ddtd, J=9.0, 8.4, 1.2, 0.6 Hz,1H), 6.56 (dd, J=8.9, 1.9 Hz, 1H), 5.38 (s, 1H), 2.21 (dt, J=2.2, 0.5Hz, 3H) ppm.

Step 3: tert-butyl2-bromo-6-[3-fluoro-2-methyl-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoate

To a stirring solution of tert-butyl2-bromo-6-fluoro-3-(trifluoromethyl)benzoate (1.66 g, 4.84 mmol) and3-fluoro-2-methyl-4-(trifluoromethoxy)phenol (1.03 g, 4.90 mmol, Example98, Step 2) in DMSO (6.5 mL) in a pressure vessel was added K₂CO₃ (1.35g, 9.77 mmol) (325 mesh). The vessel was sealed and the suspensionheated at 100° C. for 16 hours. After cooling to room temperature, themixture was diluted with ethyl acetate and washed with water and brine.The organic layer was dried over Na₂SO₄, filtered and concentrated invacuo. The crude material was purified by silica gel chromatography(0-10% ethyl acetate/hexanes) to provide tert-butyl2-bromo-6-[3-fluoro-2-methyl-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoate(1.49 g, 58%). ESI-MS m z calc. 532.01, found 476.9 (M-tert-butyl+1)+;LC/MS retention time (Method A): 0.92 minutes.

Step 4: tert-butyl6-[3-fluoro-2-methyl-4-(trifluoromethoxy)phenoxy]-2-methyl-3-(trifluoromethyl)benzoate

A mixture of tert-butyl2-bromo-6-[3-fluoro-2-methyl-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoate(1.49 g, 2.79 mmol), Cs₂CO₃ (2.736 g, 8.397 mmol) and methylboronic acid(841 mg, 14.1 mmol) in dioxane (22 mL) was sparged with nitrogen for 10minutes. Pd(dppf)Cl₂ (52 mg, 0.071 mmol) was added and the mixturestirred at 90° C. for 4 hours. The mixture was filtered over Celite andthe solids washed with dioxane. The filtrate was concentrated in vacuo,then partitioned between heptane/MTBE 4:1 (100 mL) and water (100 mL)and the layers separated. The organic layer was washed with water andbrine, dried over Na₂SO₄, filtered and concentrated in vacuo to providetert-butyl6-[3-fluoro-2-methyl-4-(trifluoromethoxy)phenoxy]-2-methyl-3-(trifluoromethyl)benzoate(1.23 g, 94%) as a yellow liquid. ESI-MS m z calc. 468.12, found 413.1(M-tert-butyl+1)+; LC/MS retention time (Method A): 0.96 minutes.

Step 5:6-[3-fluoro-2-methyl-4-(trifluoromethoxy)phenoxy]-2-methyl-3-(trifluoromethyl)benzoicacid

A solution of tert-butyl6-[3-fluoro-2-methyl-4-(trifluoromethoxy)phenoxy]-2-methyl-3-(trifluoromethyl)benzoate(1.23 g, 2.63 mmol) in 2-propanol (6 mL) was treated with aqueous HCl (3mL of 6 M, 18 mmol) and stirred at 90° C. for 1 hour. The mixture wasallowed to cool and partitioned between ethyl acetate and water. Thelayers were separated and the aqueous layer was extracted withadditional ethyl acetate (3×). The combined organic layers were washedwith water and brine, dried over Na₂SO₄, filtered through Celite andconcentrated in vacuo. Purification by reverse phase HPLC (1-99%acetonitrile/5 mM HCl) provided6-[3-fluoro-2-methyl-4-(trifluoromethoxy)phenoxy]-2-methyl-3-(trifluoromethyl)benzoicacid (579.3 mg, 53%) as an orange viscous liquid. ESI-MS m z calc.412.05, found 413.1 (M+1)⁺; LC/MS retention time (Method C): 2.86minutes.

Step 6:6-[3-fluoro-2-methyl-4-(trifluoromethoxy)phenoxy]-2-methyl-3-(trifluoromethyl)benzoyl

To a solution of6-[3-fluoro-2-methyl-4-(trifluoromethoxy)phenoxy]-2-methyl-3-(trifluoromethyl)benzoicacid (480 mg, 1.16 mmol) and DMF (15 μL, 0.19 mmol) in dichloromethane(8 mL) at 0° C. was added oxalyl chloride (285 μL, 3.26 mmol) dropwiseunder nitrogen. The ice bath was removed after 10 minutes and themixture was stirred at room temperature for 1 hour. The solvent wasconcentrated in vacuo to provide6-[3-fluoro-2-methyl-4-(trifluoromethoxy)phenoxy]-2-methyl-3-(trifluoromethyl)benzoylchloride.

Step 7: methyl4-[[6-[3-fluoro-2-methyl-4-(trifluoromethoxy)phenoxy]-2-methyl-3-(trifluoromethyl)benzoyl]amino]-5-methyl-pyridine-2-carboxylate(hydrochloride salt)

To a solution of methyl 4-amino-5-methyl-pyridine-2-carboxylate (46 mg,0.28 mmol, Preparation 1) and DIEA (121 μL, 0.697 mmol) in NMP (500 μL)at 0° C. was added a solution of6-[3-fluoro-2-methyl-4-(trifluoromethoxy)phenoxy]-2-methyl-3-(trifluoromethyl)benzoylchloride (60 mg, 0.14 mmol) in NMP (500 μL). The mixture was stirred at75° C. for 11 hours. The mixture was filtered and purified by reversephase HPLC (1-99% acetonitrile/5 mM HCl) to provide methyl4-[[6-[3-fluoro-2-methyl-4-(trifluoromethoxy)phenoxy]-2-methyl-3-(trifluoromethyl)benzoyl]amino]-5-methyl-pyridine-2-carboxylate(hydrochloride salt) (14.2 mg, 18%). ESI-MS m/z calc. 560.12, found561.2 (M+1)⁺; LC/MS retention time (Method C): 2.81 minutes. ¹H NMR (400MHz, DMSO-d₆) δ 10.57 (s, 1H), 8.54 (s, 1H), 8.53 (s, 1H), 7.76 (d,J=8.8 Hz, 1H), 7.50 (t, J=8.9 Hz, 1H), 7.05 (dd, J=9.1, 1.8 Hz, 1H),6.85 (d, J=8.8 Hz, 1H), 3.87 (s, 3H), 2.49 (s, 3H), 2.28 (s, 3H), 2.15(d, J=2.1 Hz, 3H) ppm.

Step 8:4-[[6-[3-fluoro-2-methyl-4-(trifluoromethoxy)phenoxy]-2-methyl-3-(trifluoromethyl)benzoyl]amino]-5-methyl-pyridine-2-carboxamide(288)

Methyl4-[[6-[3-fluoro-2-methyl-4-(trifluoromethoxy)phenoxy]-2-methyl-3-(trifluoromethyl)benzoyl]amino]-5-methyl-pyridine-2-carboxylate(hydrochloride salt) (7.7 mg, 0.013 mmol) was dissolved in a solution ofammonia in methanol (2 mL of 7 M, 14 mmol) and stirred at 75° C. for 1hour in a sealed vial, then at room temperature for 60 hours.Purification by reverse phase HPLC (10-99% acetonitrile/5 mM HCl)provided4-[[6-[3-fluoro-2-methyl-4-(trifluoromethoxy)phenoxy]-2-methyl-3-(trifluoromethyl)benzoyl]amino]-5-methyl-pyridine-2-carboxamide(Hydrochloride salt) (6.0 mg, 80%). ESI-MS m z calc. 545.12, found 546.2(M+1)⁺; LC/MS retention time (Method C): 2.71 minutes. ¹H NMR (400 MHz,DMSO-d₆) δ 10.54 (s, 1H), 8.48 (s, 1H), 8.46 (s, 1H), 8.07 (d, J=2.9 Hz,1H), 7.75 (d, J=8.8 Hz, 1H), 7.61 (d, J=2.9 Hz, 1H), 7.51 (t, J=8.9 Hz,1H), 7.06 (dd, J=9.1, 1.8 Hz, 1H), 6.84 (d, J=8.8 Hz, 1H), 2.49 (s, 3H),2.27 (s, 3H), 2.15 (d, J=2.0 Hz, 3H) ppm.

Example 995-[[6-[3-fluoro-2-methyl-4-(trifluoromethoxy)phenoxy]-2-methyl-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(289)

This compound was made in an analogous fashion to the synthesis ofcompound 288 in Example 98, except employing5-aminopyridine-2-carboxamide in the amide formation step (Step 7). Theyield of5-[[6-[3-fluoro-2-methyl-4-(trifluoromethoxy)phenoxy]-2-methyl-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamideafter purification was 48.5 mg (66%). ESI-MS m z calc. 531.10, found532.1 (M+1)⁺; LC/MS retention time (Method C): 2.72 minutes. ¹H NMR (400MHz, DMSO-d₆) δ 11.23 (s, 1H), 8.85 (d, J=2.4 Hz, 1H), 8.30 (dd, J=8.5,2.5 Hz, 1H), 8.04 (d, J=8.5 Hz, 1H), 8.01 (s, 1H), 7.77 (d, J=8.9 Hz,1H), 7.56 (s, 1H), 7.49 (t, J=8.9 Hz, 1H), 7.05 (dd, J=9.1, 1.8 Hz, 1H),6.87 (d, J=8.8 Hz, 1H), 2.46 (s, 3H), 2.12 (d, J=2.1 Hz, 3H) ppm.

Example 1004-[[6-[3-fluoro-2-methyl-4-(trifluoromethoxy)phenoxy]-2-methyl-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(290)

This compound was made in an analogous fashion to the synthesis ofcompound 288 in Example 98, except employing4-aminopyridine-2-carboxamide in the amide formation step (Step 5). Theyield of4-[[6-[3-fluoro-2-methyl-4-(trifluoromethoxy)phenoxy]-2-methyl-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamidewas 19.7 mg (27% yield). ESI-MS m z calc. 531.10, found 532.1 (M+1)⁺;LC/MS retention time (Method C): 2.73 minutes. ¹H NMR (400 MHz, DMSO-d₆)δ 11.36 (s, 1H), 8.54 (d, J=5.5 Hz, 1H), 8.36 (d, J=2.1 Hz, 1H), 8.12(s, 1H), 7.83 (dd, J=5.5, 2.2 Hz, 1H), 7.77 (d, J=8.9 Hz, 1H), 7.67 (s,1H), 7.49 (t, J=8.9 Hz, 1H), 7.06 (dd, J=9.1, 1.8 Hz, 1H), 6.86 (d,J=8.8 Hz, 1H), 2.45 (s, 3H), 2.11 (d, J=2.0 Hz, 3H) ppm.

Example 1014-[[2-fluoro-6-[3-fluoro-2-methyl-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]-5-methyl-pyridine-2-carboxamide(291)

Step 1:2-fluoro-6-[3-fluoro-2-methyl-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoicacid

To a pressure flask was added6-bromo-2-fluoro-3-(trifluoromethyl)benzoic acid (663 mg, 2.31 mmol),3-fluoro-2-methyl-4-(trifluoromethoxy)phenol (450 mg, 2.14 mmol, seeExample 98, Step 2), Cs₂CO₃ (1.07 g, 3.28 mmol) and toluene (15 mL). Themixture was bubbled with nitrogen for 10 minutes, then copper (I) iodide(420 mg, 2.21 mmol) added. The flask was flushed with nitrogen, cappedand heated at 100° C. with vigorous stirring for 16 hours. The mixturewas allowed to cool, and then diluted with ethyl acetate and water. Thewater layer was acidified with 1 M aqueous HCl and the product extractedwith ethyl acetate (3×). The combined organic layers were washed withbrine, dried over Na₂SO₄ and concentrated in vacuo. Purification byreverse phase HPLC (10-99% acetonitrile/5 mM HCl) provided2-fluoro-6-[3-fluoro-2-methyl-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoicacid (437 mg, 49%). ESI-MS m z calc. 416.03, found 417.1 (M+1)⁺; LC/MSretention time (Method B): 1.92 minutes. ¹H NMR (400 MHz, DMSO-d₆) δ14.22 (s, 1H), 7.81 (t, J=8.6 Hz, 1H), 7.50 (t, J=8.8 Hz, 1H), 7.06 (dd,J=9.2, 1.8 Hz, 1H), 6.85 (d, J=8.8 Hz, 1H), 2.15 (d, J=2.1 Hz, 3H) ppm.

Step 2: methyl4-[[2-fluoro-6-[3-fluoro-2-methyl-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]-5-methyl-pyridine-2-carboxylate

A solution of2-fluoro-6-[3-fluoro-2-methyl-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoicacid (40 mg, 0.096 mmol), DMF (0.6 μL, 0.007 mmol) and dichloromethane(0.5 mL) was cooled to 0° C. in an ice bath. To this solution was addedoxalyl chloride (17 μL, 0.19 mmol). The resulting mixture was stirred inthe ice bath for 10 minutes and then at room temperature for 50 minutes.The mixture was concentrated in vacuo. The resulting acid chloride wasdissolved in NMP (0.4 mL) and slowly added to a solution of methyl4-amino-5-methyl-pyridine-2-carboxylate (48 mg, 0.29 mmol, Preparation1), DIEA (100 μL, 0.58 mmol) and NMP (0.2 mL). The mixture was allowedto warm to room temperature and stirred for 16 hours at roomtemperature. The mixture was filtered and purified by reverse phase HPLC(acetonitrile/5 mM HCl gradient) to provide methyl4-[[2-fluoro-6-[3-fluoro-2-methyl-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]-5-methyl-pyridine-2-carboxylate(28 mg, 52%). ESI-MS m z calc. 564.09, found 565.2 (M+1)⁺; LC/MSretention time (Method B): 1.94 minutes. ¹H NMR (400 MHz, DMSO-d₆) δ10.70 (s, 1H), 8.56 (s, 1H), 8.49 (s, 1H), 7.87 (t, J=8.6 Hz, 1H), 7.53(t, J=8.9 Hz, 1H), 7.13 (d, J=9.3 Hz, 1H), 6.87 (d, J=8.9 Hz, 1H), 3.88(s, 3H), 2.30 (s, 3H), 2.16 (d, J=2.1 Hz, 3H) ppm.

Step 3:4-[[2-fluoro-6-[3-fluoro-2-methyl-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]-5-methyl-pyridine-2-carboxamide(291)

Methyl4-[[2-fluoro-6-[3-fluoro-2-methyl-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]-5-methyl-pyridine-2-carboxylate(20 mg, 0.03544 mmol) was dissolved in a solution of ammonia in methanol(3 mL of 7 M, 21 mmol) and stirred at room temperature for 48 hours. Thesolvent was removed in vacuo and the residue was purified by reversephase HPLC (acetonitrile/5 mM HCl gradient). Additional purification bySFC ([R, R]-Whelk-O (150×2.1 mm) column; eluting with 8% methanol (20 mMammonia)/92% CO₂) provided4-[[2-fluoro-6-[3-fluoro-2-methyl-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]-5-methyl-pyridine-2-carboxamide(5.6 mg, 29%). ESI-MS m z calc. 549.09, found 550.1 (M+1)⁺; LC/MSretention time (Method B): 1.35 minutes. ¹H NMR (400 MHz, DMSO-d₆) δ10.69 (s, 1H), 8.48 (s, 2H), 8.09 (s, 1H), 7.86 (t, J=8.6 Hz, 1H), 7.63(s, 1H), 7.55 (t, J=8.8 Hz, 1H), 7.16 (d, J=9.1 Hz, 1H), 6.86 (d, J=8.9Hz, 1H), 2.30 (s, 3H), 2.17 (d, J=2.1 Hz, 3H) ppm.

Example 1025-[[2-fluoro-6-[3-fluoro-2-methyl-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(292)

This compound was made in an analogous fashion to the synthesis ofcompound 288 in Example 98, except employing5-aminopyridine-2-carboxamide in the amide formation step (Step 7). Theyield of5-[[2-fluoro-6-[3-fluoro-2-methyl-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamidewas 33.8 mg (66% yield). ESI-MS m z calc. 535.08, found 536.3 (M+1)⁺;LC/MS retention time (Method B): 1.87 minutes. ¹H NMR (400 MHz, DMSO-d₆)δ 11.42 (s, 1H), 8.83 (d, J=2.4 Hz, 1H), 8.27 (dd, J=8.6, 2.5 Hz, 1H),8.09-8.00 (m, 2H), 7.88 (t, J=8.7 Hz, 1H), 7.58 (d, J=2.8 Hz, 1H), 7.52(t, J=8.8 Hz, 1H), 7.13 (dd, J=9.1, 1.8 Hz, 1H), 6.91 (d, J=8.9 Hz, 1H),2.14 (d, J=2.1 Hz, 3H) ppm.

Example 1034-[[2-fluoro-6-[3-fluoro-2-methyl-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(293)

A mixture of methyl4-[[2,6-difluoro-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxylate(100 mg, 0.278 mmol, see US 2019/0016671, Example 169, Step 3, which isincorporated by reference), 3-fluoro-2-methyl-4-(trifluoromethoxy)phenol(56 mg, 0.27 mmol, see Example 98, Step 2) and Cs₂CO₃ (142 mg, 0.4358mmol) in DMF (3 mL) and stirred overnight at 70° C. The mixture waspartitioned between ethyl acetate and brine and the layers separated.The organic layer was washed with brine, dried over MgSO₄, filtered andconcentrated in vacuo. Purification by reverse phase HPLC (47-95%acetonitrile/0.1% ammonium hydroxide) provided methyl4-[[2-fluoro-6-[3-fluoro-2-methyl-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxylate.The material was dissolved in a solution of ammonia in methanol (2 mL of7 M, 14 mmol) and stirred overnight at room temperature. The mixture wasconcentrated in vacuo to provide4-[[2-fluoro-6-[3-fluoro-2-methyl-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(32.7 mg, 22%). ESI-MS m z calc. 535.08, found 536.1 (M+1)⁺; 534.2(M−1)⁻; LC/MS retention time (Method E): 3.39 minutes. ¹H NMR (400 MHz,CDCl₃) δ 10.28 (s, 1H), 8.60-8.51 (m, 2H), 8.30-8.24 (m, 1H), 7.89 (d,J=4.6 Hz, 1H), 7.66 (t, J=8.3 Hz, 1H), 7.16 (t, J=8.7 Hz, 1H), 6.91 (dd,J=9.0, 1.9 Hz, 1H), 6.64 (d, J=8.8 Hz, 1H), 4.92 (d, J=4.6 Hz, 1H), 2.18(d, J=2.1 Hz, 3H) ppm.

Example 1044-[[2-fluoro-6-[3-fluoro-2-methyl-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethoxy)benzoyl]amino]pyridine-2-carboxamide(294)

Step 1:2-fluoro-6-[3-fluoro-2-methyl-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethoxy)benzoicacid

A mixture of 3-fluoro-2-methyl-4-(trifluoromethoxy)phenol (690 mg, 2.79mmol, see Example 98, Step 2),6-bromo-2-fluoro-3-(trifluoromethoxy)benzoic acid (702 mg, 2.32 mmol,see Example 90, Step 1) and Cs₂CO₃ (1.8 g, 5.5 mmol) in toluene (12 mL)was heated at 100° C. for 10 minutes, then treated with copper (I)iodide (90 mg, 0.47 mmol) and stirred at 100° C. for 1 hour. The mixturewas acidified with 2 M aqueous HCl and partitioned between ethyl acetateand water. The organic layer was washed with brine, dried over MgSO₄,filtered and concentrated in vacuo to provide crude2-fluoro-6-[3-fluoro-2-methyl-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethoxy)benzoicacid (1.14 g, 114%). ESI-MS m z calc. 432.02, no ionization observed;LC/MS retention time (Method F): 0.63 minutes. ¹H NMR (400 MHz, CDCl₃) δ7.37 (ddq, J=9.4, 8.2, 1.2 Hz, 1H), 7.22-7.14 (m, 1H), 6.78 (dd, J=9.0,2.0 Hz, 1H), 6.58 (dd, J=9.2, 1.9 Hz, 1H), 2.24 (d, J=2.2 Hz, 3H) ppm.The isolated product was used without further purification.

Step 2:4-[[2-fluoro-6-[3-fluoro-2-methyl-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethoxy)benzoyl]amino]pyridine-2-carboxamide(294)

A mixture of2-fluoro-6-[3-fluoro-2-methyl-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethoxy)benzoicacid (200 mg, 0.463 mmol) and DMF (3.5 μL, 0.045 mmol) indichloromethane (3 mL) at 0° C. was treated dropwise with oxalylchloride (170 μL, 1.95 mmol). The mixture was stirred for 1 hour, andthen concentrated in vacuo. The residue was redissolved indichloromethane (3 mL) and added dropwise to a stirring solution ofmethyl 4-aminopyridine-2-carboxylate (82 mg, 0.51 mmol), DIPEA (250 μL,1.44 mmol) and DMAP (57 mg, 0.47 mmol) in dichloromethane (3 mL). Themixture was stirred overnight and concentrated in vacuo. The residue wasdissolved in a solution of ammonia in methanol (7 M) and stirred for 3days. The mixture was concentrated and purified by HPLC (47-95%acetonitrile/0.1% ammonium hydroxide) to provide4-[[2-fluoro-6-[3-fluoro-2-methyl-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethoxy)benzoyl]amino]pyridine-2-carboxamide(28.0 mg, 11%). ESI-MS m z calc. 551.07, found 552.1 (M+1)⁺; 550.1(M−1)⁻; LC/MS retention time (Method F): 0.96 minutes. ¹H NMR (400 MHz,DMSO-d₆) δ 11.46 (s, 1H), 8.55 (dd, J=5.4, 0.6 Hz, 1H), 8.30-8.25 (m,1H), 8.10 (d, J=2.9 Hz, 1H), 7.82-7.63 (m, 3H), 7.47 (t, J=8.8 Hz, 1H),7.03 (dd, J=9.1, 1.8 Hz, 1H), 6.93 (dd, J=9.2, 1.6 Hz, 1H), 2.15 (d,J=2.1 Hz, 3H) ppm.

Example 1054-[[3-chloro-2-fluoro-6-[3-fluoro-2-methyl-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(295)

Step 1:3-chloro-2-fluoro-6-[3-fluoro-2-methyl-4-(trifluoromethoxy)phenoxy]benzoicacid

A mixture of 6-bromo-3-chloro-2-fluoro-benzoic acid (1000 mg, 3.946mmol, see Example 96, step 1),3-fluoro-2-methyl-4-(trifluoromethoxy)phenol (862 mg, 4.10 mmol, seeExample 98, Step 2) and Cs₂CO₃ (1.49 g, 4.57 mmol) in toluene (15 mL)was stirred for 10 minutes then treated with copper (I) iodide (290 mg,1.52 mmol). The mixture was heated at 100° C. with vigorous stirringovernight. The mixture was cooled, acidified with 2 M aqueous HCl andfiltered and partitioned with ethyl acetate. The organic layer waswashed with brine, dried over MgSO₄, filtered and concentrated toprovide3-chloro-2-fluoro-6-[3-fluoro-2-methyl-4-(trifluoromethoxy)phenoxy]benzoicacid (1.5 g, 86%). ¹H NMR (400 MHz, CDCl₃) δ 9.90 (s, 1H), 7.44 (dd,J=9.0, 8.0 Hz, 1H), 7.22-7.13 (m, 1H, obscured by residual toluene),6.76 (dd, J=9.0, 1.9 Hz, 1H), 6.56 (dd, J=9.0, 1.6 Hz, 1H), 2.23 (d,J=2.2 Hz, 3H) ppm.

Step 2:4-[[3-chloro-2-fluoro-6-[3-fluoro-2-methyl-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(295)

A solution of3-chloro-2-fluoro-6-[3-fluoro-2-methyl-4-(trifluoromethoxy)phenoxy]benzoicacid (200 mg, 0.418 mmol) and DMF (33 μL, 0.43 mmol) in dichloromethane(3 mL) at 0° C. was treated dropwise with oxalyl chloride (150 μL, 1.720mmol). The mixture was stirred for 1 hour and concentrated in vacuo. Theresidue was redissolved in dichloromethane (3 mL) and added dropwise toa stirring solution of methyl 4-aminopyridine-2-carboxylate (75 mg, 0.47mmol), DIPEA (230 μL, 1.32 mmol) and DMAP (52 mg, 0.43 mmol) indichloromethane (3 mL). The mixture was stirred overnight thenconcentrated. The residue was dissolved in dichloromethane (3 mL) andtreated with a solution of ammonia in methanol (7 M). The mixture wasstirred for three days, then concentrated and purified by reverse phaseHPLC (47-95% acetonitrile/0.1% ammonium hydroxide) to provide4-[[3-chloro-2-fluoro-6-[3-fluoro-2-methyl-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(32.5 mg, 15%). ESI-MS m z calc. 501.05, found 502.1 (M+1)⁺; 500.1(M−1)⁻; LC/MS retention time (Method F): 0.92 minutes. ¹H NMR (400 MHz,CDCl₃) δ 9.90 (s, 1H), 8.58-8.48 (m, 2H), 8.24 (d, J=2.4 Hz, 1H), 7.93(d, J=4.6 Hz, 1H), 7.47 (dd, J=9.0, 8.0 Hz, 1H), 7.12 (t, J=8.6 Hz, 1H),6.81 (dd, J=9.0, 1.9 Hz, 1H), 6.62 (dd, J=8.9, 1.5 Hz, 1H), 5.09 (d,J=4.6 Hz, 1H), 2.18 (d, J=2.2 Hz, 3H) ppm.

Example 1064-[[6-[2-chloro-3-fluoro-4-(trifluoromethoxy)phenoxy]-2-fluoro-3-(trifluoromethyl)benzoyl]amino]-5-methyl-pyridine-2-carboxamide(296)

Step 1: 2-[3-fluoro-4-(trifluoromethoxy)phenoxy]tetrahydropyran

To a stirring solution of 3-fluoro-4-(trifluoromethoxy)phenol (10.0 g,51.0 mmol) and concentrated HCl (43 μL of 12 M, 0.52 mmol) anddichloromethane (150 mL) was added a solution of 3,4-dihydro-2H-pyran(7.0 mL, 76.7 mmol) in dichloromethane (40 mL) dropwise. The mixture wasstirred at room temperature for 2 hours, and then washed with 1 Maqueous NaOH (2×). The organic layer was dried over MgSO₄, filtered andconcentrated in vacuo. Silica gel chromatography (0-20% ethylacetate/hexanes gradient) provided2-[3-fluoro-4-(trifluoromethoxy)phenoxy]tetrahydropyran (10.4 g, 73%) asa colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 7.19 (td, J=8.8, 1.2 Hz, 1H),6.92 (dd, J=11.8, 2.8 Hz, 1H), 6.81 (ddd, J=9.1, 2.9, 1.6 Hz, 1H), 5.37(t, J=3.2 Hz, 1H), 3.85 (ddd, J=11.3, 9.9, 3.1 Hz, 1H), 3.62 (dtd,J=11.4, 4.1, 1.4 Hz, 1H), 2.04-1.91 (m, 1H), 1.89-1.83 (m, 2H),1.77-1.55 (m, 3H) ppm.

Step 2: 2-[2-chloro-3-fluoro-4-(trifluoromethoxy)phenoxy]tetrahydropyran

A solution of 2-[3-fluoro-4-(trifluoromethoxy)phenoxy]tetrahydropyran(3.0 g, 10.7 mmol) in THF (48 mL) was cooled to −78° C. To this solutionwas added a solution of (diisopropylamino)lithium (7.0 mL of 2.0 M inTHF/heptane/ethylbenzene, 14.0 mmol) over 5 minutes. After stirring for1 hour at −78° C., a suspension of N-chlorosuccinimide (2.15 g, 16.1mmol) in THF (1 mL) was added dropwise. The resulting mixture wasstirred at −78° C. for 30 minutes then slowly warmed up to roomtemperature. The mixture was stirred at room temperature for 16 hours,and then diluted with saturated aqueous NH₄Cl solution. The layers wereseparated and the aqueous layer was extracted with diethyl ether (3×).The combined organic layers were dried over Na₂SO₄, filtered andconcentrated in vacuo. Silica gel chromatography (ethyl acetate/hexanesgradient) provided a colorless oil, which was further purified byreverse phase HPLC (acetonitrile/water gradient) to provide2-[2-chloro-3-fluoro-4-(trifluoromethoxy)phenoxy]tetrahydropyran (1.0 g,30%) as a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 7.15 (ddd, J=9.4,8.2, 1.3 Hz, 1H), 6.98 (dd, J=9.4, 2.1 Hz, 1H), 5.51 (t, J=2.8 Hz, 1H),3.84 (td, J=11.0, 3.0 Hz, 1H), 3.67-3.60 (m, 1H), 2.14-1.94 (m, 2H),1.95-1.83 (m, 1H), 1.80-1.58 (m, 3H) ppm.

Step 3: 2-chloro-3-fluoro-4-(trifluoromethoxy)phenol

2-[2-Chloro-3-fluoro-4-(trifluoromethoxy)phenoxy]tetrahydropyran (2.5 g,7.9 mmol) was dissolved in a solution of HCl in dioxane (40 mL of 4.0 M,160 mmol). The resulting mixture was stirred at room temperature for 16hours. The mixture was concentrated in vacuo. The residue was treatedwith 2 M aqueous NaOH (pH˜10) and washed with diethyl ether. The aqueouslayer was acidified with 1 M aqueous HCl and extracted with diethylether (3×). The combined organic layers were dried over MgSO₄, filteredand concentrated in vacuo to provide2-chloro-3-fluoro-4-(trifluoromethoxy)phenol (1.7 g, 93%) as a colorlessoil. ¹H NMR (400 MHz, CDCl₃) δ 7.16 (ddd, J=9.3, 8.0, 1.1 Hz, 1H), 6.84(dd, J=9.2, 2.2 Hz, 1H), 5.67 (s, 1H) ppm.

Step 4:6-[2-chloro-3-fluoro-4-(trifluoromethoxy)phenoxy]-2-fluoro-3-(trifluoromethyl)benzoicacid

To a pressure flask was added6-bromo-2-fluoro-3-(trifluoromethyl)benzoic acid (818 mg, 2.85 mmol),2-chloro-3-fluoro-4-(trifluoromethoxy)phenol (610 mg, 2.65 mmol), Cs₂CO₃(1.3 g, 4.0 mmol) and toluene (20 mL). The mixture was bubbled withnitrogen for 10 minutes, then copper (I) iodide (520 mg, 2.73 mmol)added. The flask was flushed with nitrogen, capped and heated at 100° C.with vigorous stirring for 16 hours. The mixture was allowed to cool,and then partitioned between water and ethyl acetate and the layersseparated. The water layer was acidified with 1 M aqueous HCl and theproduct extracted into ethyl acetate (3×). The combined organic layerswere washed with brine, dried over Na₂SO₄ and concentrated in vacuo.Purification by reverse phase HPLC (acetonitrile/water gradient)provided6-[2-chloro-3-fluoro-4-(trifluoromethoxy)phenoxy]-2-fluoro-3-(trifluoromethyl)benzoicacid (724 mg, 63%). ¹H NMR (400 MHz, DMSO-d₆) δ 14.26 (s, 1H), 7.86 (t,J=8.6 Hz, 1H), 7.69 (t, J=8.8 Hz, 1H), 7.25 (dd, J=9.3, 2.1 Hz, 1H),7.03 (d, J=8.8 Hz, 1H) ppm.

Step 5: methyl4-[[6-[2-chloro-3-fluoro-4-(trifluoromethoxy)phenoxy]-2-fluoro-3-(trifluoromethyl)benzoyl]amino]-5-methyl-pyridine-2-carboxylate

A solution of6-[2-chloro-3-fluoro-4-(trifluoromethoxy)phenoxy]-2-fluoro-3-(trifluoromethyl)benzoicacid (40 mg, 0.092 mmol), DMF (0.2 μL, 0.002 mmol) and dichloromethane(0.4 mL) was cooled to 0° C. in an ice bath. To this solution was addedoxalyl chloride (5.3 μL, 0.061 mmol). The resulting mixture was stirredat room temperature for 20 minutes then concentrated in vacuo. Theresulting acid chloride was dissolved in NMP (400 μL) and slowly addedto a solution of methyl 4-amino-5-methyl-pyridine-2-carboxylate (46 mg,0.27 mmol, Preparation 1) and DIEA (10.6 μL, 0.061 mmol) in NMP (200 μL)at 0° C. The mixture was allowed to warm to room temperature and stirredfor 16 hours. Purification by reverse phase HPLC (acetonitrile/5 mM HClgradient) provided methyl4-[[6-[2-chloro-3-fluoro-4-(trifluoromethoxy)phenoxy]-2-fluoro-3-(trifluoromethyl)benzoyl]amino]-5-methyl-pyridine-2-carboxylate(34 mg, 63%). ESI-MS m z calc. 584.04, found 585.1 (M+1)⁺; LC/MSretention time (Method B): 1.45 minutes. ¹H NMR (400 MHz, DMSO-d₆) δ10.71 (s, 1H), 8.57 (s, 1H), 8.47 (s, 1H), 7.91 (t, J=8.6 Hz, 1H), 7.73(t, J=8.8 Hz, 1H), 7.34 (dd, J=9.3, 2.0 Hz, 1H), 7.07 (d, J=8.8 Hz, 1H),3.88 (s, 3H), 2.31 (s, 3H) ppm.

Step 6:4-[[6-[2-chloro-3-fluoro-4-(trifluoromethoxy)phenoxy]-2-fluoro-3-(trifluoromethyl)benzoyl]amino]-5-methyl-pyridine-2-carboxamide(296)

To a suspension of methyl4-[[6-[2-chloro-3-fluoro-4-(trifluoromethoxy)phenoxy]-2-fluoro-3-(trifluoromethyl)benzoyl]amino]-5-methyl-pyridine-2-carboxylate(30 mg, 0.05 mmol) in methanol (0.5 mL) was added a solution ammonia inmethanol (2 mL of 7 M, 14 mmol). The mixture was stirred for 24 hours,and then concentrated in vacuo. The residue was purified by reversephase HPLC (30-99% acetonitrile/5 mM HCl), followed by SFC purification([R, R]-Whelk-O column, eluting with 10% methanol (20 mM ammonia), 90%CO₂) to provide4-[[6-[2-chloro-3-fluoro-4-(trifluoromethoxy)phenoxy]-2-fluoro-3-(trifluoromethyl)benzoyl]amino]-5-methyl-pyridine-2-carboxamide(12.9 mg, 44%) as a white solid. ESI-MS m z calc. 569.04, found 570.0(M+1)⁺; LC/MS retention time (Method B): 1.22 minutes. ¹H NMR (400 MHz,DMSO-d₆) δ 10.67 (s, 1H), 8.46 (d, J=18.0 Hz, 2H), 8.07 (d, J=2.7 Hz,1H), 7.90 (t, J=8.6 Hz, 1H), 7.74 (t, J=8.9 Hz, 1H), 7.64-7.59 (m, 1H),7.35 (dd, J=9.4, 2.0 Hz, 1H), 7.05 (d, J=8.8 Hz, 1H), 2.29 (s, 3H) ppm.

Example 1075-[[6-[2-chloro-3-fluoro-4-(trifluoromethoxy)phenoxy]-2-fluoro-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(297)

This compound was made in an analogous fashion to the synthesis ofcompound 296 in Example 106, except employing5-aminopyridine-2-carboxamide in Step 5. The yield of5-[[2-fluoro-6-[3-fluoro-2-methyl-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamidewas 36.5 mg (70% yield). ESI-MS m z calc. 555.02, found 556.1 (M+1)⁺;LC/MS retention time (Method B): 1.40 minutes. ¹H NMR (400 MHz, DMSO-d₆)δ 11.46 (s, 1H), 8.83 (d, J=2.4 Hz, 1H), 8.27 (dd, J=8.6, 2.5 Hz, 1H),8.09-8.01 (m, 2H), 7.92 (t, J=8.6 Hz, 1H), 7.72 (t, J=8.8 Hz, 1H), 7.58(s, 1H), 7.35 (dd, J=9.3, 2.0 Hz, 1H), 7.08 (d, J=8.8 Hz, 1H) ppm.

Example 1084-[[6-[2-chloro-3-fluoro-4-(trifluoromethoxy)phenoxy]-2-fluoro-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(298)

This compound was made in an analogous fashion to the synthesis ofcompound 296 in Example 106, except employing4-aminopyridine-2-carboxamide in Step 5. The yield of4-[[6-[2-chloro-3-fluoro-4-(trifluoromethoxy)phenoxy]-2-fluoro-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamidewas 25.4 mg (49% yield). ESI-MS m z calc. 555.02, found 556.0 (M+1)⁺;LC/MS retention time (Method B): 1.44 minutes. ¹H NMR (400 MHz, DMSO-d₆)δ 11.49 (s, 1H), 8.56 (d, J=5.5 Hz, 1H), 8.28 (d, J=2.2 Hz, 1H), 8.11(d, J=2.7 Hz, 1H), 7.92 (t, J=8.6 Hz, 1H), 7.80 (dd, J=5.5, 2.2 Hz, 1H),7.72 (t, J=8.8 Hz, 1H), 7.67 (d, J=2.9 Hz, 1H), 7.35 (dd, J=9.3, 2.1 Hz,1H), 7.07 (d, J=8.8 Hz, 1H) ppm.

Example 1094-[[6-(3,4-difluoro-2-methoxy-phenoxy)-2-fluoro-4-methoxy-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(299)

Step 1: methyl4-[[6-bromo-2-fluoro-4-methoxy-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxylate

DMF (50 μL, 0.65 mmol) was added to a solution of oxalyl chloride (2.0mL, 23 mmol) and 6-bromo-2-fluoro-4-methoxy-3-(trifluoromethyl)benzoicacid (2.0 g, 6.3 mmol, see US 2019/0016671, Example 129, Step 3, whichis incorporated by reference) in dichloromethane (40 mL) at 0° C. andthe resulting mixture stirred at room temperature for 2 hours. Thesolvent was removed in vacuo and redissolved in dichloromethane (40 mL).Methyl 4-aminopyridine-2-carboxylate (1.0 g, 6.6 mmol) and TEA (2.0 mL,14 mmol) were added and the resulting mixture stirred at roomtemperature for 2 hours. The mixture was concentrated in vacuo and theresidue purified by silica gel chromatography (0-70% ethylacetate/petroleum ether) to provide methyl4-[[6-bromo-2-fluoro-4-methoxy-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxylate(1.37 g, 48%) as a pale yellow solid. ESI-MS m z calc. 449.98, found453.3 (M+1)⁺; 449.3 (M−1)⁻; LC/MS retention time (Method F): 0.81minutes. ¹H NMR (500 MHz, DMSO-d₆) δ 11.40 (s, 1H), 8.66 (d, J=5.4 Hz,1H), 8.38 (d, J=2.0 Hz, 1H), 7.82 (dd, J=5.4, 2.2 Hz, 1H), 7.59 (s, 1H),4.02 (s, 3H), 3.90 (s, 3H) ppm.

Step 2:4-[[6-bromo-2-fluoro-4-methoxy-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide

A solution of ammonia in methanol (20 mL of 7 M, 140 mmol) was added tomethyl4-[[6-bromo-2-fluoro-4-methoxy-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxylate(1.35 g, 2.992 mmol) and the resulting mixture was stirred at roomtemperature over 3 days. The mixture was concentrated in vacuo toprovide4-[[6-bromo-2-fluoro-4-methoxy-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(1.25 g, 96%) as a yellow powder. ESI-MS m z calc. 434.98, found 436.4(M+1)⁺; 434.5 (M−1)⁻; LC/MS retention time (Method E): 0.76 minutes.

Step 3:4-[[6-(3,4-difluoro-2-methoxy-phenoxy)-2-fluoro-4-methoxy-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(299)

A mixture of4-[[6-bromo-2-fluoro-4-methoxy-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(350 mg, 0.803 mmol), 3,4-difluoro-2-methoxy-phenol (120 mg, 0.749 mmol)and Cs₂CO₃ (280 mg, 0.859 mmol) in toluene (10 mL) was bubbled withnitrogen for 10 minutes, then copper (I) iodide (53 mg, 0.28 mmol) wasadded. The mixture was heated at 100° C. with vigorous stirring for 1hour. The mixture was cooled to room temperature and partitioned betweenwater (30 mL) and ethyl acetate (30 mL). The layers were separated andthe aqueous layer was extracted with additional ethyl acetate (2×50 mL).The combined organic extracts were washed with brine, dried over MgSO₄,filtered and concentrated. Silica gel column chromatography (0-100%ethyl acetate/heptane), followed by reverse phase HPLC purification(47-95% acetonitrile/0.1% ammonium hydroxide) provided4-[[6-(3,4-difluoro-2-methoxy-phenoxy)-2-fluoro-4-methoxy-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(18.2 mg, 4%) as a white powder. ESI-MS m z calc. 515.09, found 516.4(M+1)⁺; 514.4 (M−1)⁻; LC/MS retention time (Method E): 3.09 minutes. ¹HNMR (500 MHz, DMSO-d₆) δ 11.34 (s, 1H), 8.55 (d, J=5.5 Hz, 1H), 8.31 (d,J=2.1 Hz, 1H), 8.14 (d, J=2.6 Hz, 1H), 7.82 (dd, J=5.5, 2.2 Hz, 1H),7.69 (d, J=2.8 Hz, 1H), 7.26 (td, J=9.7, 8.3 Hz, 1H), 7.13 (ddd, J=9.4,5.1, 2.1 Hz, 1H), 6.44 (s, 1H), 3.86 (d, J=1.1 Hz, 3H), 3.81 (s, 3H)ppm.

Example 110 and Example 1114-[[6-(3,4-difluoro-2-methoxy-phenoxy)-4-methoxy-2-(methylamino)-3-(trifluoromethyl)benzoyl]amino]-N-methyl-pyridine-2-carboxamide(300)

And4-[[6-(3,4-difluoro-2-methoxy-phenoxy)-2-fluoro-4-methoxy-3-(trifluoromethyl)benzoyl]amino]-N-methyl-pyridine-2-carboxamide(301)

Step 1:6-(3,4-difluoro-2-methoxy-phenoxy)-2-fluoro-4-methoxy-3-(trifluoromethyl)benzoicacid

A mixture of 6-bromo-2-fluoro-4-methoxy-3-(trifluoromethyl)benzoic acid(6.5 g, 20.5 mmol, see Example 109, Step 3),3,4-difluoro-2-methoxy-phenol (3.0 g, 19 mmol) and Cs₂CO₃ (7.0 g, 21.5mmol), in toluene (30 mL) was bubbled with nitrogen for 10 minutes, thencopper (I) iodide (1.37 g, 7.19 mmol) was added. The mixture was heatedat 100° C. with vigorous stirring for 1.5 hours. The mixture was cooledto ambient temperature, acidified with 1 M aqueous HCl (15 mL) andfiltered. The mixture was then extracted with ethyl acetate (3×50 mL).The combined organic extracts were washed with brine (10 mL), dried overMgSO₄, filtered and concentrated in vacuo. The residue was purified bysilica gel chromatography (0-100% ethyl acetate/heptane) to provide6-(3,4-difluoro-2-methoxy-phenoxy)-2-fluoro-4-methoxy-3-(trifluoromethyl)benzoicacid (6.0 g, 81%). ESI-MS m z calc. 396.04, found 396.8 (M+1)⁺; 395.0(M−1)⁻; LC/MS retention time (Method E): 2.07 minutes.

Step 2: methyl4-[[6-(3,4-difluoro-2-methoxy-phenoxy)-2-fluoro-4-methoxy-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxylate

To a solution of6-(3,4-difluoro-2-methoxy-phenoxy)-2-fluoro-4-methoxy-3-(trifluoromethyl)benzoicacid (500 mg, 1.26 mmol) and DMF (10 μL, 0.13 mmol) in dichloromethane(6 mL) at 0° C. was added oxalyl chloride (250 μL, 2.87 mmol). Themixture was warmed to room temperature over 30 minutes, thenconcentrated in vacuo. The residue was redissolved in dichloromethane (3mL) and the solution was added to a solution of methyl4-aminopyridine-2-carboxylate (240 mg, 1.577 mmol) and TEA (250 μL,1.794 mmol) in dichloromethane (3 mL) at 0° C. The resulting mixture wasstirred and warmed to room temperature over 2 hours. The mixture wasdiluted with aqueous NH₄Cl solution and extracted with dichloromethane(2×5 mL). The combined organic extracts were dried over MgSO₄, filteredand concentrated in vacuo. Purification by silica gel chromatography(0-100% ethyl acetate/heptane) provided methyl4-[[6-(3,4-difluoro-2-methoxy-phenoxy)-2-fluoro-4-methoxy-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxylate(200 mg, 30%). ESI-MS m z calc. 530.09, found 531.0 (M+1)⁺; 529.1(M−1)⁻; LC/MS retention time (Method E): 3.21 minutes.

Step 3:4-[[6-(3,4-difluoro-2-methoxy-phenoxy)-4-methoxy-2-(methylamino)-3-(trifluoromethyl)benzoyl]amino]-N-methyl-pyridine-2-carboxamide(300) and4-[[6-(3,4-difluoro-2-methoxy-phenoxy)-2-fluoro-4-methoxy-3-(trifluoromethyl)benzoyl]amino]-N-methyl-pyridine-2-carboxamide(301)

Methyl4-[[6-(3,4-difluoro-2-methoxy-phenoxy)-2-fluoro-4-methoxy-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxylate(100 mg, 0.189 mmol) was dissolved in a solution of methylamine (20 mLof 2 M, 40 mmol) and stirred for 60 hours at room temperature. Themixture was concentrated in vacuo to afford a mixture of products. Themixture was purified by reverse phase HPLC (acetonitrile+0.05%TFA/water+0.05% TFA gradient) to provide the following isolatedcomponents:4-[[6-(3,4-difluoro-2-methoxy-phenoxy)-4-methoxy-2-(methylamino)-3-(trifluoromethyl)benzoyl]amino]-N-methyl-pyridine-2-carboxamide(16.3 mg, 16%) (300). ESI-MS m z calc. 540.14, found 541.1 (M+1)⁺; 539.2(M−1)⁻; LC/MS retention time (Method E): 3.12 minutes. ¹H NMR (500 MHz,DMSO-d₆) δ 11.09 (s, 1H), 8.71 (d, J=4.9 Hz, 1H), 8.49 (d, J=5.5 Hz,1H), 8.30 (d, J=2.5 Hz, 1H), 7.84 (dd, J=5.4, 2.1 Hz, 1H), 7.27-7.12 (m,1H), 7.06-6.89 (m, 1H), 5.85 (s, 1H), 5.60 (s, 1H), 3.81 (s, 3H), 3.65(s, 3H), 2.84 (s, 3H), 2.81 (d, J=4.9 Hz, 3H) ppm.

and

4-[[6-(3,4-difluoro-2-methoxy-phenoxy)-2-fluoro-4-methoxy-3-(trifluoromethyl)benzoyl]amino]-N-methyl-pyridine-2-carboxamide(301) (2.7 mg, 3%). ESI-MS m z calc. 529.10, found 530.1 (M+1)⁺; 528.2(M−1)⁻; LC/MS retention time (Method E): 3.18 minutes. ¹H NMR (400 MHz,DMSO-d₆) δ 11.34 (s, 1H), 8.82-8.73 (m, 1H), 8.55 (d, J=5.5 Hz, 1H),8.27 (d, J=2.2 Hz, 1H), 7.84 (dd, J=5.8, 2.2 Hz, 1H), 7.25 (q, J=9.3 Hz,1H), 7.20-7.08 (m, 1H), 6.44 (s, 1H), 3.86 (s, 3H), 3.81 (s, 3H), 2.82(d, J=4.7 Hz, 3H).

Example 112N-(2-carbamoyl-5-methyl-4-pyridyl)-5-(3,4-difluoro-2-methoxy-phenoxy)-3-methoxy-2-(trifluoromethyl)pyridine-4-carboxamide(302)

Step 1: ethyl5-(3,4-difluoro-2-methoxy-phenoxy)-3-fluoro-2-(trifluoromethyl)pyridine-4-carboxylate

A solution of ethyl3,5-difluoro-2-(trifluoromethyl)pyridine-4-carboxylate (1.00 g, 3.92mmol, see US 2019/0016671, Example 148, Step 1, which is incorporated byreference) and 3,4-difluoro-2-methoxy-phenol (623 mg, 3.89 mmol) in DMF(6 mL) was cooled to −10° C. Cs₂CO₃ (2.553 g, 7.836 mmol) was added tothe solution in one portion, and the mixture gradually warmed to roomtemperature and stirred for 16 hours. The mixture was diluted with water(40 mL) and extracted with ethyl acetate. The organic layer was washedwith brine, dried over Na₂SO₄, filtered and concentrated to provideethyl5-(3,4-difluoro-2-methoxy-phenoxy)-3-fluoro-2-(trifluoromethyl)pyridine-4-carboxylate(1.5 g, 97%). ESI-MS m z calc. 395.06, found 396.5 (M+1)⁺; LC/MSretention time (Method A): 0.77 minutes.

Step 2:5-(3,4-difluoro-2-methoxy-phenoxy)-3-methoxy-2-(trifluoromethyl)pyridine-4-carboxylicacid

Ethyl5-(3,4-difluoro-2-methoxy-phenoxy)-3-fluoro-2-(trifluoromethyl)pyridine-4-carboxylate(1.55 g, 3.92 mmol) was dissolved in a solution of sodium methoxide (30mL of 25% w/w in methanol, 131 mmol) and stirred at room temperature for70 minutes. Aqueous 1 M NaOH was added and the suspension heated at 45°C. until clear (˜1 hour). The mixture was concentrated in vacuo andacidified with 1 M aqueous HCl. The aqueous mixture was extracted withethyl acetate (3×). The combined extracts were washed with brine, driedover Na₂SO₄, filtered and concentrated. The colorless thick oil wastriturated with dichloromethane/hexane to obtain5-(3,4-difluoro-2-methoxy-phenoxy)-3-methoxy-2-(trifluoromethyl)pyridine-4-carboxylicacid (568 mg, 38%) as a white solid. ESI-MS m z calc. 379.05, found380.5 (M+1)⁺; LC/MS retention time (Method A): 0.61 minutes. ¹H NMR (400MHz, DMSO-d₆) δ 14.55 (br s, 1H), 8.02 (s, 1H), 7.26 (td, J=9.7, 8.3 Hz,1H), 7.14 (ddd, J=9.4, 5.1, 2.2 Hz, 1H), 3.97 (s, 3H), 3.87 (d, J=1.4Hz, 3H) ppm.

Step 4:5-(3,4-difluoro-2-methoxy-phenoxy)-3-methoxy-2-(trifluoromethyl)pyridine-4-carbonylchloride

To a solution of5-(3,4-difluoro-2-methoxy-phenoxy)-3-methoxy-2-(trifluoromethyl)pyridine-4-carboxylicacid (156 mg, 0.411 mmol) and DMF (3 μL, 0.04 mmol) in dichloromethane(1.5 mL) was added oxalyl chloride (52 μL, 0.60 mmol) dropwise at 0° C.The mixture was stirred at room temperature for 30 minutes until gasevolution had ceased. The solvent was removed in vacuo to afford5-(3,4-difluoro-2-methoxy-phenoxy)-3-methoxy-2-(trifluoromethyl)pyridine-4-carbonylchloride.

Step 5: methyl4-[[5-(3,4-difluoro-2-methoxy-phenoxy)-3-methoxy-2-(trifluoromethyl)pyridine-4-carbonyl]amino]-5-methyl-pyridine-2-carboxylate

A solution of methyl 4-amino-5-methyl-pyridine-2-carboxylate (41 mg,0.25 mmol, Preparation 1) and DIEA (106 μL, 0.609 mmol) in NMP (0.5 mL)at 0° C. was treated dropwise with a solution of5-(3,4-difluoro-2-methoxy-phenoxy)-3-methoxy-2-(trifluoromethyl)pyridine-4-carbonylchloride (81 mg, 0.2037 mmol) in dichloromethane (1.5 mL). The mixturewas allowed to warm to room temperature over 16 hours. The mixture wasconcentrated to provide methyl4-[[5-(3,4-difluoro-2-methoxy-phenoxy)-3-methoxy-2-(trifluoromethyl)pyridine-4-carbonyl]amino]-5-methyl-pyridine-2-carboxylate(92 mg, 86%). ESI-MS m z calc. 527.11, found 528.6 (M+1)⁺; LC/MSretention time (Method A): 0.65 minutes.

Step 6:N-(2-carbamoyl-5-methyl-4-pyridyl)-5-(3,4-difluoro-2-methoxy-phenoxy)-3-methoxy-2-(trifluoromethyl)pyridine-4-carboxamide(302)

Methyl4-[[5-(3,4-difluoro-2-methoxy-phenoxy)-3-methoxy-2-(trifluoromethyl)pyridine-4-carbonyl]amino]-5-methyl-pyridine-2-carboxylate(75 mg, 0.14 mmol) was dissolved in a solution of ammonia in methanol(3.0 mL of 7 M, 21 mmol) and stirred for 2 hours at room temperature,then treated with additional ammonia in methanol (3.0 mL of 7 M, 21mmol) and heated at 50° C. in a sealed vial 16 hours. The mixture wascooled to room temperature and concentrated in vacuo. Purification byreverse phase HPLC (10-99% acetonitrile/5 mM HCl) providedN-(2-carbamoyl-5-methyl-4-pyridyl)-5-(3,4-difluoro-2-methoxy-phenoxy)-3-methoxy-2-(trifluoromethyl)pyridine-4-carboxamide(30.6 mg, 42%). ESI-MS m/z calc. 512.11, found 513.1 (M+1)⁺; LC/MSretention time (Method C): 2.14 minutes. ¹H NMR (400 MHz, DMSO-d₆) δ10.70 (s, 1H), 8.49 (s, 2H), 8.07 (s, 1H), 7.63 (d, J=2.8 Hz, 1H),7.33-7.24 (m, 1H), 7.16 (ddd, J=9.4, 5.2, 2.1 Hz, 1H), 7.09 (br s, 1H),4.03 (s, 3H), 3.89 (d, J=1.4 Hz, 3H), 2.32 (s, 3H) ppm.

Example 1134-[[2,3-difluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(303)

Step 1: 3-fluoro-2-methoxy-4-(trifluoromethoxy)phenol

To a solution of 1-bromo-3-fluoro-2-methoxy-4-(trifluoromethoxy)benzene(900 mg, 2.52 mmol) in dioxane (4 mL) was addedtris(dibenzylideneacetone)dipalladium (116 mg, 0.127 mmol), tBuXPhos(112 mg, 0.264 mmol) and KOH (425 mg, 7.58 mmol) followed by water (2mL). The mixture was heated at 90° C. overnight, then cooled to roomtemperature and partitioned between MTBE (20 mL) and water (10 mL). Theaqueous layer was separated and acidified to pH 1 by addition of 2 Maqueous HCl. The aqueous layer was then extracted with MTBE (2×20 mL).The combined organics were washed with brine (10 mL), dried over MgSO₄,filtered and concentrated in vacuo to provide3-fluoro-2-methoxy-4-(trifluoromethoxy)phenol (456 mg, 75%) as an orangeoil. ESI-MS m z calc. 226.03, found 225.6 (M−1)⁻; LC/MS retention time(Method F): 0.87 minutes. ¹H NMR (400 MHz, DMSO-d₆) δ 10.18 (s, 1H),7.14-7.01 (m, 1H), 6.73 (dd, J=9.2, 2.2 Hz, 1H), 3.83 (s, 3H) ppm.

Step 2:2,3-difluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]benzoicacid

6-Bromo-2,3-difluoro-benzoic acid (2.0 g, 8.4 mmol) and3-fluoro-2-methoxy-4-(trifluoromethoxy)phenol (2.36 g, 10.4 mmol,) weredissolved in toluene (40 mL) and the solution was purged with nitrogen(3×vacuum/nitrogen flush). Cs₂CO₃ (5.54 g, 17.0 mmol) was added and themixture was stirred for 5 minutes. Copper (I) iodide (325 mg, 1.76 mmol)was added and the mixture stirred at 100° C. overnight. The mixture wasacidified to pH=2 with 1 M aqueous HCl and partitioned between ethylacetate and water. The aqueous layer was extracted with additional ethylacetate (2×). The combined organic extracts were washed with brine,dried over MgSO₄, filtered and concentrated in vacuo. Purification bysilica gel chromatography (0-50% ethyl acetate/heptane) provided2,3-difluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]benzoicacid (1.63 g, 45%) as a yellow waxy solid. ESI-MS m z calc. 382.03,found 381.3 (M−1)⁻; LC/MS retention time (Method F): 0.55 minutes. H NMR(500 MHz, CDCl₃) δ 7.23 (td, J=9.3, 8.5 Hz, 1H), 7.02 (tt, J=7.9, 1.3Hz, 1H), 6.82 (dd, J=9.2, 2.3 Hz, 1H), 6.57 (ddd, J=9.3, 3.5, 2.0 Hz,1H), 3.93 (d, J=1.4 Hz, 3H) ppm.

Step 3: methyl4-[[2,3-difluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxylate

One drop of DMF (5 μL, 0.06 mmol) was added to a solution of2,3-difluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]benzoicacid (298 mg, 0.702 mmol) in dichloromethane (5 mL) at 0° C., followedby a dropwise addition of oxalyl chloride (190 μL, 2.18 mmol). Themixture was allowed to warm to room temperature and stirred for 1 hour.The mixture was concentrated in vacuo, dissolved in dichloromethane (3mL) and added dropwise to a solution of methyl4-aminopyridine-2-carboxylate (120 mg, 0.789 mmol) and TEA (300 μL, 2.15mmol) in dichloromethane (3.5 mL) at 0° C. The mixture allowed to cometo room temperature and stirred overnight. The mixture diluted withdichloromethane and water and filtered through a phase separatorcartridge. The organic filtrate was concentrated in vacuo. Due to onlypartial conversion to product, the residue was dissolved in acetonitrile(2.7 mL) and treated with 1-methylimidazole (140 μL, 1.76 mmol) followedby [chloro(dimethylamino)methylene]-dimethyl-ammonium (PhosphorusHexafluoride Ion) (238 mg, 0.848 mmol). The mixture was stirred at roomtemperature for 30 minutes and concentrated in vacuo. The mixture waspartitioned between dichloromethane and water and filtered through aphase separator. The organic filtrate was concentrated in vacuo andpurified by silica gel chromatography (30-100% ethyl acetate/heptane) toprovide methyl4-[[2,3-difluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxylate(105.4 mg, 29%) as a waxy solid. ESI-MS m z calc. 516.08, found 517.4(M+1)⁺; 515.4 (M−1)⁻; LC/MS retention time (Method F): 0.92 minutes. ¹HNMR (500 MHz, CDCl₃) δ 8.90 (s, 1H), 8.69 (d, J=5.5 Hz, 1H), 8.21 (s,1H), 8.06-8.01 (m, 1H), 7.22 (t, J=8.8 Hz, 1H), 7.09 (td, J=8.3, 7.6,1.2 Hz, 1H), 7.00 (dd, J=9.2, 2.1 Hz, 1H), 6.61-6.57 (m, 1H), 4.01 (s,3H), 3.87 (d, J=2.0 Hz, 3H) ppm.

Step 4:4-[[2,3-difluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(303)

Methyl4-[[2,3-difluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxylate(105 mg, 0.203 mmol) was dissolved in a solution of ammonia in methanol(4 mL of 7 M, 28 mmol) and stirred at room temperature for 4 hours. Themixture concentrated in vacuo and purified by reverse phase HPLC (38-53%acetonitrile/0.1% ammonium hydroxide) to provide4-[[2,3-difluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(53 mg, 51%) as a white solid. ESI-MS m z calc. 501.08, found 502.5(M+1)⁺; 500.4 (M−1)⁻; LC/MS retention time (Method E): 3.09 minutes. ¹HNMR (500 MHz, CDCl₃) δ 9.12 (s, 1H), 8.52 (d, J=5.5 Hz, 1H), 8.33 (dd,J=5.5, 2.2 Hz, 1H), 8.07 (d, J=2.2 Hz, 1H), 7.83 (s, 1H), 7.21 (q, J=9.1Hz, 1H), 7.02 (tq, J=7.6, 1.3 Hz, 1H), 6.91 (dd, J=9.2, 2.2 Hz, 1H),6.59 (ddd, J=9.2, 3.5, 2.0 Hz, 1H), 5.33 (s, 1H), 3.88 (d, J=1.9 Hz, 3H)ppm.

Example 1144-[[2,3-difluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]-5-methyl-pyridine-2-carboxamide(304)

Step 1: methyl4-[[2,3-difluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]-5-methyl-pyridine-2-carboxylate

This compound was made in an analogous fashion to Example 113, Step 3,except employing methyl 4-amino-5-methyl-pyridine-2-carboxylate(Preparation 1) in place of methyl 4-aminopyridine-2-carboxylate in Step3. The yield of5-[[3-chloro-2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamideafter purification was 109 mg (29%). ESI-MS m z calc. 530.09, found531.4 (M+1)⁺; 529.4 (M−1)⁻; LC/MS retention time (Method F): 0.94minutes as a white solid. ¹H NMR (500 MHz, CDCl₃) δ 9.07 (s, 1H), 8.53(s, 1H), 8.35 (s, 1H), 7.26-7.20 (m, 1H), 7.09 (t, J=8.4 Hz, 1H), 6.98(dd, J=9.2, 2.1 Hz, 1H), 6.60-6.56 (m, 1H), 4.01 (s, 3H), 3.82 (d, J=2.0Hz, 3H), 2.29 (s, 3H) ppm.

Step 2:4-[[2,3-difluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]-5-methyl-pyridine-2-carboxamide(304)

Methyl4-[[2,3-difluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]-5-methyl-pyridine-2-carboxylate(109 mg, 0.2055 mmol) was dissolved in a solution of ammonia in methanol(4 mL of 7 M, 28 mmol) and stirred at room temperature for 5 hours. Themixture was concentrated in vacuo and redissolved in ammonia in methanol(4 mL of 7 M, 28 mmol) and stirred at room temperature for 3 days.Purification by reverse phase HPLC (38-53% acetonitrile/0.1% ammoniumhydroxide) provided4-[[2,3-difluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]-5-methyl-pyridine-2-carboxamide(51 mg, 48%) as a white solid. ESI-MS m z calc. 515.09, found 516.4(M+1)⁺; 514.4 (M−1)⁻; LC/MS retention time (Method E): 3.11 minutes. ¹HNMR (500 MHz, CDCl₃) δ 8.87 (s, 1H), 8.36 (s, 1H), 8.06 (s, 1H), 7.73(s, 1H), 7.20 (q, J=9.0 Hz, 1H), 7.09-7.02 (m, 1H), 6.95 (dd, J=9.2, 2.2Hz, 1H), 6.57 (ddd, J=9.2, 3.5, 2.0 Hz, 1H), 5.45 (s, 1H), 3.85 (d,J=1.9 Hz, 3H), 2.29 (s, 3H) ppm.

Example 1154-[[3-chloro-2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide_(305)

Step 1:3-chloro-2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]benzoicacid

A mixture of 6-bromo-3-chloro-2-fluoro-benzoic acid (2.0 g, 7.9 mmol,see US 2019/0016671, Example 82, Step 1, which is incorporated byreference), 3-fluoro-2-methoxy-4-(trifluoromethoxy)phenol (1.98 g, 8.76mmol, see Example 113, Step 1) and Cs₂CO₃ (5.14 g, 15.8 mmol) andtoluene (15 mL) in a pressure flask was bubbled with nitrogen for 10minutes, then copper (I) iodide (360 mg, 1.89 mmol) added. The flask wassealed and heated at 100° C. with vigorous stirring for 16 hours undernitrogen. The cooled mixture diluted with ethyl acetate and water, andthen acidified with 1 M aqueous HCl. The layers were separated, and theaqueous layer was extracted with additional ethyl acetate (3×). Thecombined organic layers were washed with water (2×) and brine, driedover Na₂SO₄, filtered through Celite and concentrated. Purification byreverse phase HPLC (1-99% acetonitrile/5 mM HCl) provided3-chloro-2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]benzoicacid (1.302 g, 41%). ESI-MS m/z calc. 398.00, found 399.1 (M+1)⁺; LC/MSretention time (Method B): 1.19 minutes. ¹H NMR (400 MHz, DMSO-d₆) δ7.65 (t, J=8.7 Hz, 1H), 7.32 (ddd, J=9.4, 8.1, 1.3 Hz, 1H), 7.01 (dd,J=9.3, 2.2 Hz, 1H), 6.85 (dd, J=9.1, 1.5 Hz, 1H), 3.88 (d, J=1.0 Hz, 3H)ppm.

Step 2:4-[[3-chloro-2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(305)

A solution of3-chloro-2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]benzoicacid (30 mg, 0.075 mmol) and DMF (6 μL, 0.08 mmol) in dichloromethane(200 μL) at 0° C. was treated with oxalyl dichloride (39 μL, 0.45 mmol).The mixture was stirred at 0° C. for 5 minutes and for 30 minutes atroom temperature. The mixture was concentrated in vacuo. The residue wasdissolved in NMP (250 mL) and slowly added to mixture of4-aminopyridine-2-carboxamide (20.6 mg, 0.151 mmol) and DIEA (79 μL,0.45 mmol) in NMP (250 mL) at 0° C. The mixture was allowed to warm toroom temperature and stirred for 16 hours. The mixture was filtered andpurified by reverse phase HPLC (acetonitrile/5 mM HCl gradient) toprovide4-[[3-chloro-2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(28.2 mg, 72%). ESI-MS m z calc. 517.05, found 518.1 (M+1)⁺; LC/MSretention time (Method B): 1.1 minutes. ¹H NMR (400 MHz, DMSO-d₆) δ11.42 (s, 1H), 8.54 (d, J=5.4 Hz, 1H), 8.30 (d, J=2.1 Hz, 1H), 8.10 (d,J=2.8 Hz, 1H), 7.80 (dd, J=5.5, 2.2 Hz, 1H), 7.71 (t, J=8.8 Hz, 1H),7.66 (d, J=2.8 Hz, 1H), 7.39-7.30 (m, 1H), 7.09 (dd, J=9.3, 2.1 Hz, 1H),6.89 (dd, J=9.0, 1.4 Hz, 1H), 3.84 (d, J=1.0 Hz, 3H) ppm.

Example 1165-[[3-chloro-2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(306)

This compound was made in an analogous fashion to the synthesis ofcompound 305 in Example 115, except employing5-aminopyridine-2-carboxamide in the amide formation step. The yield of5-[[3-chloro-2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamideafter purification was 29 mg (73%). ESI-MS m z calc. 517.05, found 518.0(M+1)⁺; LC/MS retention time (Method B): 1.09 minutes. ¹H NMR (400 MHz,DMSO-d₆) δ 11.36 (s, 1H), 8.83 (d, J=2.4 Hz, 1H), 8.27 (dd, J=8.6, 2.5Hz, 1H), 8.08-8.00 (m, 2H), 7.71 (t, J=8.8 Hz, 1H), 7.57 (s, 1H), 7.34(t, J=8.4 Hz, 1H), 7.09 (dd, J=9.4, 2.2 Hz, 1H), 6.91 (dd, J=9.1, 1.4Hz, 1H), 3.85 (d, J=1.0 Hz, 3H) ppm.

Example 1174-[[2,3,4-trifluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(307)

Step 1:2,3,4-trifluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]benzoicacid

A solution of 6-bromo-2,3,4-trifluoro-benzoic acid (3.0 g, 11.8 mmol) intoluene (93 mL) was bubbled with nitrogen for 10 minutes.3-Fluoro-2-methoxy-4-(trifluoromethoxy)phenol (4.0 g, 17.7 mmol, seeExample 113, Step 1) and Cs₂CO₃ (8.05 g, 24.7 mmol) were added solutionand bubbled with nitrogen for 10 minutes. Copper (I) iodide (2.32 g,12.2 mmol) was added and the mixture bubbled with nitrogen for 10minutes. The mixture was heated at 100° C. with vigorous stirring undernitrogen for 6.5 hours. The mixture was allowed to cool, partitionedbetween ethyl acetate and water and acidified with 1 M aqueous HCl. Thelayers were separated and the aqueous layer was extracted withadditional ethyl acetate (3×). The combined organic layers were washedwith water and brine, dried over Na₂SO₄, filtered through Celite andconcentrated. Purification by reverse phase HPLC (1-99% acetonitrile/5mM HCl) provided2,3,4-trifluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]benzoicacid (2.211 g, 47%). ESI-MS m z calc. 400.02, found 401.1 (M+1)⁺; LC/MSretention time (Method C): 2.56 minutes. ¹H NMR (400 MHz, DMSO-d₆) δ14.08 (s, 1H), 7.31 (t, J=8.9 Hz, 1H), 7.26-7.13 (m, 1H), 6.96 (dd,J=9.4, 2.2 Hz, 1H), 3.89 (s, 3H) ppm.

Step 2:2,3,4-trifluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]benzoylchloride

To2,3,4-trifluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]benzoicacid (100 mg, 0.250 mmol) and DMF (15 μL, 0.19 mmol) in dichloromethane(2 mL) at 0° C. was added oxalyl chloride (63 μL, 0.72 mmol) dropwiseunder nitrogen atmosphere. The ice bath was removed after 10 minutes andthe mixture was stirred at room temperature for 1 hour. The concentratedin vacuo to afford2,3,4-trifluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]benzoylchloride which was used in the next step without further purification.

Step 3:4-[[2,3,4-trifluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(307)

To a solution of 4-aminopyridine-2-carboxamide (41 mg, 0.30 mmol) andDIEA (131 μL, 0.750 mmol) in NMP (0.5 mL) at 0° C. was slowly added asolution of2,3,4-trifluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]benzoylchloride (63 mg, 0.15 mmol) in NMP (0.5 mL). The mixture was stirred atroom temperature for 19 hours. Purification by reverse phase HPLC(10-99% acetonitrile/5 mM HCl) provided4-[[2,3,4-trifluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(13.4 mg, 17%). ESI-MS m z calc. 519.07, found 520.1 (M+1)⁺; LC/MSretention time (Method C): 2.44 minutes. ¹H NMR (400 MHz, DMSO-d₆) δ11.46 (s, 1H), 8.55 (d, J=5.5 Hz, 1H), 8.28 (d, J=2.1 Hz, 1H), 8.10 (s,1H), 7.79 (dd, J=5.5, 2.1 Hz, 1H), 7.67 (s, 1H), 7.32 (t, J=8.7 Hz, 1H),7.29-7.19 (m, 1H), 7.08 (dd, J=9.4, 2.1 Hz, 1H), 3.85 (s, 3H) ppm.

Example 1185-[[2,3,4-trifluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyrimidine-2-carboxamide(308)

This compound was made in an analogous fashion to the synthesis ofcompound 307 in Example 117, except employing methyl5-aminopyrimidine-2-carboxylate in the amide formation step. The yieldof methyl5-[[2,3,4-trifluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyrimidine-2-carboxylateafter purification was 112.3 mg (42%). ESI-MS m z calc. 535.06, found536.1 (M+1)⁺; LC/MS retention time (Method A): 0.65 minutes. Analogoustreatment with methanolic ammonia provided5-[[2,3,4-trifluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyrimidine-2-carboxamide(73.8 mg, 28%) as an off-white solid. ESI-MS m z calc. 520.06, found521.1 (M+1)⁺; LC/MS retention time (Method E): 2.23 minutes. ¹H NMR (400MHz, DMSO-d₆) δ 11.56 (s, 1H), 9.14 (s, 2H), 8.13 (s, 1H), 7.74 (s, 1H),7.40-7.20 (m, 2H), 7.08 (dd, J=9.3, 2.1 Hz, 1H), 3.86 (s, 3H) ppm.

Example 1194-[[4-chloro-2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-3-methyl-benzoyl]amino]pyridine-2-carboxamide(309)

Step 1: methyl4-chloro-2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]benzoate

A mixture of methyl 4-chloro-2,6-difluoro-benzoate (1000 mg, 4.841mmol), 3-fluoro-2-methoxy-4-(trifluoromethoxy)phenol (1.07 g, 4.73 mmol,see Example 113, Step 1) and Cs₂CO₃ (2.5 g, 7.7 mmol) in DMF (40 mL) wasstirred at 70° C. for 48 hours. The mixture was partitioned betweenethyl acetate and brine and the layers separated. The organic layer waswashed with brine, dried over MgSO₄, filtered and evaporated.Purification by silica gel chromatography (0-20% ethyl acetate) providedmethyl4-chloro-2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]benzoate(540 mg, 27%). ¹H NMR (400 MHz, CDCl₃) δ 7.06 (tq, J=7.7, 1.3 Hz, 1H),6.91 (ddd, J=22.5, 9.1, 2.1 Hz, 2H), 6.56 (t, J=1.6 Hz, 1H), 3.99-3.88(m, 6H) ppm.

Step 2: methyl4-chloro-2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-3-methyl-benzoate

A solution of n-butyllithium (570 μL of 1.6 M in hexanes, 0.9120 mmol)was added to a stirring solution of diisopropylamine (120 μL, 0.856mmol) in THF (7 mL) at −78° C. The mixture was then stirred at 0° C. for20 minutes. The resulting LDA solution was added dropwise to a solutionmethyl4-chloro-2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]benzoate(250 mg, 0.606 mmol) in THF (5 mL) at −78° C. The mixture was stirred atthis temperature for 10 minutes then methyl iodide (102 μL, 1.64 mmol)was added. The mixture was stirred at −78° C. for 30 minutes thenallowed to warm to room temperature. The mixture was diluted with waterand extracted with ethyl acetate (3×). The combined organic extractswere dried over MgSO₄, filtered and concentrated in vacuo to providemethyl4-chloro-2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-3-methyl-benzoate(225 mg, 44%). ¹H NMR (400 MHz, CDCl₃) δ 6.95-6.91 (m, 1H), 6.74 (dd,J=9.2, 2.3 Hz, 1H), 6.54 (d, J=1.8 Hz, 1H), 3.86 (d, J=1.3 Hz, 3H), 3.82(s, 3H), 2.20 (d, J=2.4 Hz, 3H) ppm. The isolated product containedunreacted starting material but was taken forward to the next stepwithout additional purification.

Step 3:4-chloro-2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-3-methyl-benzoicacid

To a slurry of methyl4-chloro-2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-3-methyl-benzoate(300 mg, 0.253 mmol) in methanol (10 mL) and water (10 mL) was addedNaOH (307 mg, 7.68 mmol) and the mixture was stirred at 50° C. for 18hours. The mixture was cooled to room temperature, partiallyconcentrated in vacuo to remove the methanol, and acidified with 2 Maqueous HCl. The mixture was extracted with ethyl acetate (3×), and thecombined organic extracts were dried over MgSO₄, filtered andconcentrated in vacuo to provide4-chloro-2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-3-methyl-benzoicacid (245 mg, 30%) as a white solid. ESI-MS m z calc. 412.01, found413.0 (M+1)⁺; LC/MS retention time (Method F): 0.62 minutes.

Step 4:4-[[4-chloro-2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-3-methyl-benzoyl]amino]pyridine-2-carboxamide(309)

To a solution of4-chloro-2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-3-methyl-benzoicacid (245 mg, 0.5937 mmol) and DMF (10 μL, 0.1291 mmol) indichloromethane (2 mL) at 0° C. was carefully added oxalyl chloride (160μL, 1.834 mmol) and the mixture allowed to warmed to room temperatureover 1 hour. The mixture was concentrated in vacuo, dissolved indichloromethane (2 mL) and added dropwise to a solution of methyl4-aminopyridine-2-carboxylate (110 mg, 0.723 mmol), DMAP (1 mg, 0.008mmol) and TEA (415 μL, 2.98 mmol) in dichloromethane (2 mL) at 0° C. Theresulting mixture was stirred and warmed to ambient temperatureovernight. The mixture was diluted with water and the layers separated.The aqueous layer was extracted with additional dichloromethane (2×) andthe combined organics extracts were dried over MgSO₄, filtered andconcentrated in vacuo. A solution of ammonia (3 mL of 3 M in methanol, 9mmol) was then added to the residue and the mixture stirred overnight.The mixture was concentrated in vacuo and purified by reverse phase HPLC(47-95% acetonitrile/0.1% ammonium hydroxide) to provide4-[[4-chloro-2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-3-methyl-benzoyl]amino]pyridine-2-carboxamide(6.7 mg, 2%). ESI-MS m z calc. 531.06, found 532.1 (M+1)⁺; 530.2 (M−1)⁻;LC/MS retention time (Method E): 3.32 minutes. ¹H NMR (400 MHz, CDCl₃) δ8.86 (s, 1H), 8.54 (d, J=5.6 Hz, 1H), 8.35 (dd, J=5.6, 2.2 Hz, 1H), 7.99(d, J=2.2 Hz, 1H), 7.87 (d, J=4.6 Hz, 1H), 7.09 (ddd, J=9.0, 7.7, 1.3Hz, 1H), 6.99 (dd, J=9.2, 2.2 Hz, 1H), 6.65 (d, J=1.8 Hz, 1H), 5.47 (s,1H), 3.91 (d, J=2.1 Hz, 3H), 2.33 (d, J=2.5 Hz, 3H) ppm.

Example 1204-[[3-cyclobutyl-2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(310)

Step 1:3-bromo-2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]benzoicacid

To a pressure flask was added 3-bromo-2-fluoro-6-iodo-benzoic acid (2.0g, 5.8 mmol), 3-fluoro-2-methoxy-4-(trifluoromethoxy)phenol (1.31 g,5.79 mmol, see Example 113, Step 1), Cs₂CO₃ (2.83 g, 8.69 mmol) andtoluene (36 mL). The mixture was bubbled with nitrogen for 15 minutes,then copper (I) iodide (1.10 g, 5.78 mmol) was added. The mixture washeated at 100° C. with vigorous stirring for 16 hours under nitrogen.The cooled mixture was partitioned between ethyl acetate and water, andthe water layer acidified with 1 M aqueous HCl. The layers wereseparated, and the aqueous layer extracted with additional ethyl acetate(3×). The combined organic extracts were dried over Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by reverse phasechromatography (acetonitrile/5 mM HCl) to provide3-bromo-2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]benzoicacid (1.57 g, 61%). ESI-MS m z calc. 441.95, found 445.15 (M+1)⁺; LC/MSretention time (Method A): 0.7 minutes. ¹H NMR (400 MHz, CDCl₃) δ 7.55(dd, J=9.0, 7.5 Hz, 1H), 7.04 (ddd, J=9.3, 7.8, 1.5 Hz, 1H), 6.89 (dd,J=9.2, 2.2 Hz, 1H), 6.50 (dd, J=8.9, 1.5 Hz, 1H), 3.92 (d, J=1.5 Hz, 3H)ppm.

Step 2: tert-butyl3-bromo-2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]benzoate

A mixture of3-bromo-2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]benzoicacid (1570 mg, 3.543 mmol), tert-butoxycarbonyl tert-butyl carbonate(1158 mg, 5.306 mmol), DMAP (88 mg, 0.72 mmol), and t-BuOH (5 mL) washeated at 90° C. for 1 hour. The mixture was cooled and additionaltert-butoxycarbonyl tert-butyl carbonate (1158 mg, 5.306 mmol) added.The mixture was stirred at 90° C. for 10 minutes, then cooled to roomtemperature and concentrated in vacuo. The residue was purified bysilica gel chromatography (1-10% ethyl acetate/hexanes) to providetert-butyl3-bromo-2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]benzoate(1.65 g, 93%). ¹H NMR (400 MHz, CDCl₃) δ 7.48 (dd, J=8.9, 7.6 Hz, 1H),6.99 (tt, J=7.8, 1.2 Hz, 1H), 6.76 (dd, J=9.2, 2.3 Hz, 1H), 6.52 (dd,J=8.9, 1.5 Hz, 1H), 3.95 (d, J=1.2 Hz, 3H), 1.52 (s, 9H) ppm.

Step 3: tert-butyl3-cyclobutyl-2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]benzoate

A mixture of tert-butyl3-bromo-2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]benzoate(330 mg, 0.661 mmol) and Pd(t-Bu₃P)₂ (16 mg, 0.031 mmol) in THF (2.75mL) at 0° C. under nitrogen was slowly treated with a solution ofcyclobutylzinc bromide (2.6 mL of 0.5 M, 1.3 mmol) in THF. The mixturewas allowed to warm to room temperature over 1 hour, then diluted with 1M aqueous HCl and extracted with dichloromethane (2×). The combinedorganic extracts were dried over Na₂SO₄, filtered and concentrated. Theresidue was purified by silica gel chromatography (1-15% ethylacetate/hexanes) to provide tert-butyl3-cyclobutyl-2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]benzoate(215 mg, 69%). ¹H NMR (400 MHz, CDCl₃) δ 7.21 (t, J=8.4 Hz, 1H), 6.94(ddd, J=9.2, 7.9, 1.3 Hz, 1H), 6.66 (dd, J=9.3, 2.3 Hz, 1H), 6.62 (dd,J=8.6, 1.2 Hz, 1H), 3.98 (d, J=1.0 Hz, 3H), 3.70 (p, J=8.6 Hz, 1H),2.44-2.29 (m, 2H), 2.25-1.97 (m, 3H), 1.94-1.81 (m, 1H), 1.48 (s, 9H)ppm.

Step 4:3-cyclobutyl-2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]benzoicacid

To a solution of tert-butyl3-cyclobutyl-2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]benzoate(205 mg, 0.432 mmol) in THF (8 mL) and water (0.3 mL, 16.65 mmol) at 0°C. was added TFA (8 mL, 103.8 mmol) dropwise over approximately 4minutes. The ice bath was removed and the solution stirred at roomtemperature for 2.5 hours. The mixture was concentrated in vacuo toprovide3-cyclobutyl-2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]benzoicacid (175 mg, 92%). ESI-MS m z calc. 418.08, found 419.28 (M+1)⁺; LC/MSretention time (Method B): 1.98 minutes. ¹H NMR (400 MHz, CDCl₃) δ 7.28(t, J=8.5 Hz, 1H), 7.00 (ddd, J=9.2, 7.9, 1.3 Hz, 1H), 6.81 (dd, J=9.2,2.2 Hz, 1H), 6.58 (dd, J=8.7, 1.3 Hz, 1H), 3.93 (d, J=1.3 Hz, 3H), 3.71(p, J=8.8 Hz, 1H), 2.41-2.31 (m, 2H), 2.21-1.99 (m, 3H), 1.88 (td,J=7.9, 3.0 Hz, 1H) ppm.

Step 5:4-[[3-cyclobutyl-2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(310)

To a solution of3-cyclobutyl-2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]benzoicacid (50 mg, 0.12 mmol) in dichloromethane (2 mL) at 0° C. was added DMF(2 μL, 0.03 mmol) followed by the dropwise addition of oxalyl chloride(21 μL, 0.24 mmol). The mixture was stirred at 0° C. for 10 minutes thenat room temperature for 4 hours. The mixture was concentrated in vacuoto afford the acid chloride. The acid chloride was dissolved in 2-MeTHF(2 mL) and added dropwise to a solution of methyl4-aminopyridine-2-carboxylate (20 mg, 0.13 mmol) and DIEA (53 μL, 0.30mmol) in 2-MeTHF (800 μL). The mixture was heated at 60° C. for 16hours. The cooled mixture was diluted with ethyl acetate and washed with1 M aqueous HCl (2×) and brine. The organic phase was dried over Na₂SO₄,filtered and concentrated in vacuo. The residue was purified by silicagel chromatography (ethyl acetate/hexanes gradient) to provide methyl4-[[3-cyclobutyl-2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxylate.The material was stirred in a solution of ammonia in methanol (7 mL of 7M, 49 mmol) at room temperature for 16 hours. The mixture wasconcentrated in vacuo to provide4-[[3-cyclobutyl-2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(31 mg, 48%). ESI-MS m z calc. 537.13, found 538.34 (M+1)⁺; LC/MSretention time (Method B): 1.90 minutes. ¹H NMR (400 MHz, CDCl₃) δ 8.78(s, 1H), 8.51 (d, J=5.6 Hz, 1H), 8.41-8.31 (m, 1H), 7.95 (d, J=2.2 Hz,1H), 7.91 (s, 1H), 7.29 (d, J=8.4 Hz, 1H), 7.05 (t, J=8.5 Hz, 1H), 6.94(dd, J=9.3, 2.1 Hz, 1H), 6.57 (d, J=8.6 Hz, 1H), 5.45 (s, 1H), 3.84 (d,J=1.8 Hz, 3H), 3.71 (q, J=8.8 Hz, 1H), 2.37 (m, 2H), 2.11 (m, 3H), 1.88(m, 1H) ppm.

Example 1214-[[2,2-difluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-1,3-benzodioxole-5-carbonyl]amino]pyridine-2-carboxamide(311)

Step 1: ethyl 2-bromo-4,5-dimethoxy-benzoate

A solution of 2-bromo-4,5-dimethoxy-benzoic acid (30.0 g, 115 mmol) andsulfuric acid (2.8 g, 1.5 mL, 28 mmol) in ethanol (300 mL) was heated toreflux and stirred for 72 hours. The mixture was concentrated toapproximately 20 mL in vacuo, diluted with saturated aqueous NaHCO₃ (300mL) and extracted with ethyl acetate (3×300 mL). The combined organicphases were washed with brine (300 mL), dried over Na₂SO₄, filtered andconcentrated to provide ethyl 2-bromo-4,5-dimethoxy-benzoate (27.97 g,83%) as a yellow solid. ESI-MS m z calc. 288.00, no ionization observed;LC/MS retention time (Method N): 4.98 minutes.

Step 2: ethyl 2-bromo-4,5-dihydroxy-benzoate

To a solution of ethyl 2-bromo-4,5-dimethoxy-benzoate (28.0 g, 96.8mmol) in dichloromethane (500 mL) at −78° C. under nitrogen was addedBBr₃ (79.2 g, 30 mL, 316 mmol) dropwise. The mixture was allowed toslowly warm to room temperature and stirred overnight, after which itwas cautiously added into absolute ethanol at 0° C. The mixture wasevaporated and the residue was partitioned between ethyl acetate (1 L)and 1 M aqueous potassium phosphate buffer with pH=7 (1 L). The organicphase was separated, washed with brine (500 mL), dried over Na₂SO₄,filtered and concentrated in vacuo. The residue was recrystallized fromethyl acetate/hexanes to provide ethyl 2-bromo-4,5-dihydroxy-benzoate(20.7 g, 80%) as an off-white solid. ESI-MS m z calc. 259.97, noionization observed; LC/MS retention time (Method N): 3.65 minutes.

Step 3: ethyl 6-bromo-2-thioxo-1,3-benzodioxole-5-carboxylate

A solution of imidazole (2.816 g, 41.37 mmol) in dichloromethane (100mL) at 0° C. was treated dropwise with thiophosgene (1.28 g, 0.85 mL,11.1 mmol). The mixture was allowed to stir for 15 minutes and thentreated portion-wise with ethyl 2-bromo-4,5-dihydroxy-benzoate (2.7 g,10.342 mmol). The mixture was allowed to slowly warm to room temperatureand stir for 2 hours. The mixture was washed with saturated aqueousNaHCO₃ (100 mL) and the layers separated. The organic phase was driedover Na₂SO₄, filtered and concentrated in vacuo to provide ethyl6-bromo-2-thioxo-1,3-benzodioxole-5-carboxylate (2.95 g, 89%) as anoff-white solid. ESI-MS m z calc. 301.92, no ionization observed; LC/MSretention time (Method N): 5.95 minutes.

Step 4: ethyl 6-bromo-2,2-difluoro-1,3-benzodioxole-5-carboxylate

A solution of ethyl 6-bromo-2-thioxo-1,3-benzodioxole-5-carboxylate(19.1 g, 63.0 mmol) in dichloromethane (500 mL) was cooled to −40° C.using a dry ice/acetonitrile bath and treated with HF-pyridine (100 g,90.9 mL, 718.81 mmol) followed by the portion-wise addition ofN-iodosuccinimide (42.53 g, 189.0 mmol). The mixture was stirred at −40°C. for 1 hour, then diluted with saturated aqueous NaHSO₃ (5 mL) andwater (30 mL). The organic phase was separated, dried over Na₂SO₄,filtered and concentrated in vacuo. Purification by silica gelchromatography (5% ethyl acetate/hexanes) provided ethyl6-bromo-2,2-difluoro-1,3-benzodioxole-5-carboxylate (9.8 g, 50%) as acolorless oil. ESI-MS m z calc. 309.95, found 311.6 (M+1)⁺; LC/MSretention time (Method N): 6.34 minutes

Step 5: 6-bromo-2,2-difluoro-1,3-benzodioxole-5-carboxylic acid

To a solution of ethyl6-bromo-2,2-difluoro-1,3-benzodioxole-5-carboxylate (9.8 g, 31.7 mmol)in methanol (100 mL) and water (11.5 g, 11.5 mL, 638 mmol) was addedLiOH monohydrate (13.3 g, 317 mmol). The mixture was stirred 15 minutesthen concentrated in vacuo. The residue was diluted with water (250 mL)and washed with diethyl ether (3×250 mL). The aqueous phase wasacidified with 3 M aqueous HCl until pH=1 and extracted with ethylacetate (3×300 mL). The combined organic extracts were dried over MgSO₄,filtered and concentrated in vacuo to provide6-bromo-2,2-difluoro-1,3-benzodioxole-5-carboxylic acid (7.74 g, 87%) asan off white solid. ¹H NMR (500 MHz, DMSO-d₆) δ 7.92 (s, 1H), 7.84 (s,1H) ppm. ESI-MS m z calc. 279.92, no ionization observed; LC/MSretention time (Method Q): 2.01 minutes.

Step 6:2,2-difluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-1,3-benzodioxole-5-carboxylicacid

A mixture of 6-bromo-2,2-difluoro-1,3-benzodioxole-5-carboxylic acid(2.0 g, 7.1 mmol) in toluene (45 mL) was bubbled with nitrogen for 10minutes. 3-Fluoro-2-methoxy-4-(trifluoromethoxy)phenol (2.516 g, 11.13mmol, see Example 113, Step 1) and Cs₂CO₃ (5.14 g, 15.8 mmol) were addedand the mixture bubbled with nitrogen for 10 minutes. Copper (I) iodide(317 mg, 1.66 mmol) was added to the mixture and bubbled with nitrogenfor 10 minutes. The mixture was then heated at 100° C. under nitrogenwith vigorous stirring for 72 hours. The cooled mixture was partitionedbetween ethyl acetate and water, and acidified with 1 M aqueous HCl. Thelayers were separated, and the aqueous layer was extracted withadditional ethyl acetate (3×). The combined organic extracts were washedwith water and brine, dried over Na₂SO₄, filtered through Celite andconcentrated in vacuo. The residue was purified by reverse phase HPLC(1-99% acetonitrile/5 mM HCl) to provide2,2-difluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-1,3-benzodioxole-5-carboxylicacid (1.085 g, 36%) as a yellow solid. ESI-MS m z calc. 426.02, found427.3 (M+1)⁺; LC/MS retention time (Method C): 2.74 minutes. ¹H NMR (400MHz, DMSO-d₆) δ 13.27 (s, 1H), 7.89 (s, 1H), 7.46 (s, 1H), 7.21 (t,J=8.8 Hz, 1H), 6.68 (dd, J=9.4, 2.1 Hz, 1H), 3.94 (s, 3H) ppm.

Step 7:4-[[2,2-difluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-1,3-benzodioxole-5-carbonyl]amino]pyridine-2-carboxamide(311)

To a solution of2,2-difluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-1,3-benzodioxole-5-carboxylicacid (70 mg, 0.16 mmol) and DMF (15 μL, 0.19 mmol) in dichloromethane(2.0 mL) at 0° C. was added oxalyl chloride (41 μL, 0.47 mmol) dropwiseunder a nitrogen atmosphere. The ice bath was removed after 10 minutesand the mixture was stirred at room temperature for 1 hour. The mixturewas concentrated in vacuo to afford2,2-difluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-1,3-benzodioxole-5-carbonylchloride. The acid chloride was suspended in 2-MeTHF (1 mL), cooled to0° C., and treated with a suspension of 4-aminopyridine-2-carboxamide(34.8 mg, 0.254 mmol) in 2-methyltetrahydrofuran (1.0 mL) and DIEA (72μL, 0.4134 mmol) at 0° C. The mixture was stirred at 75° C. for 21hours. The mixture was concentrated in vacuo and purified using reversephase HPLC (1-99% acetonitrile/5 mM HCl) to provide4-[[2,2-difluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-1,3-benzodioxole-5-carbonyl]amino]pyridine-2-carboxamide(7.0 mg, 8%) as a white solid. ESI-MS m z calc. 545.07, found 546.1(M+1)⁺; LC/MS retention time (Method C): 2.61 minutes. ¹H NMR (400 MHz,DMSO-d₆) δ 10.99 (s, 1H), 8.49 (d, J=5.5 Hz, 1H), 8.28 (d, J=2.1 Hz,1H), 8.07 (d, J=2.9 Hz, 1H), 7.88 (s, 1H), 7.79 (dd, J=5.6, 2.2 Hz, 1H),7.62 (d, J=2.8 Hz, 1H), 7.45 (s, 1H), 7.26 (t, J=8.7 Hz, 1H), 6.91 (dd,J=9.4, 2.1 Hz, 1H), 3.86 (s, 3H) ppm.

Example 1224-[[6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-3-(trifluoromethyl)benzoyl]amino]-5-methyl-pyridine-2-carboxamide(312)

Step 1. 2-bromo-6-fluoro-3-(trifluoromethyl)benzoic acid

Diisopropylamine (49.96 g, 69.2 mL, 493.7 mmol) was diluted intetrahydrofuran (1000 mL) and the mixture cooled to −20° C.n-Butyllithium (181 mL of 2.5 M in hexanes, 452 mmol) was added over 30minutes and the mixture was stirred at −20° C. for 30 minutes. Thesolution was cooled to −78° C. and treated with a solution of2-bromo-4-fluoro-1-(trifluoromethyl)benzene (100 g, 411.5 mmol) intetrahydrofuran (100 mL) over 30 minutes. The mixture was stirred 1hour, then carbon dioxide (181 g, 4.11 mol) pellets (dry ice) added over20 minutes at −78° C. The mixture was stirred at −78° C. for 30 minutes,and then warmed to 0° C. over 1 hour. The mixture was diluted with water(200 mL) and MTBE (200 mL) and the aqueous layer adjusted to pH 2 with 3M aqueous HCl (250 mL). The phases were separated and the aqueous phasewas extracted with additional MTBE (3×200 mL). The combined organiclayers were washed with brine (250 mL), dried over anhydrous Na₂SO₄ andfiltered. The solution was concentrated in vacuo, then redissolved inMTBE (200 mL) and a solution of 2 M aqueous NaOH (300 mL) was added.Phases were separated and the aqueous phase washed with MTBE (2×100 mL).The aqueous solution was acidified with 12 M aqueous HCl (100 mL) andextracted with MTBE (3×100 mL). The combined organic layers were washedwith brine (250 mL), dried over anhydrous Na₂SO₄ and concentrated invacuo to provide 2-bromo-6-fluoro-3-(trifluoromethyl)benzoic acid (111.7g, 89%) as a beige solid. ESI-MS m z calc. 285.93, found 570.8 (2M−1)⁻.LC/MS retention time (Method O): 1.19 minutes. ¹H NMR (400 MHz, DMSO-d₆)δ 14.84-14.11 (m, 1H), 8.00 (dd, J=9.0, 5.6 Hz, 1H), 7.62 (t, J=8.7 Hz,1H) ppm. ¹⁹F NMR (377 MHz, DMSO-d₆) δ −60.63 (s, 3F), −107.91 (s, 1F)ppm.

Step 2: tert-butyl 2-bromo-6-fluoro-3-(trifluoromethyl)benzoate

To a stirring suspension of MgSO₄ (8484 g, 70.48 mol) in dichloromethane(380 mL) under nitrogen atmosphere was slowly added H₂SO₄ (9.3 mL of100% w/w, 174.5 mmol) via syringe. The mixture was stirred at roomtemperature for 30 minutes. Solid2-bromo-6-fluoro-3-(trifluoromethyl)benzoic acid (50 g, 174 mmol) wasslowly added to the stirring solution, followed by the dropwise additionof a solution of tert-butanol (83 mL, 867.8 mmol) in dichloromethane (15mL) over 1 hour. The mixture was stirred at room temperature for 24hours. The mixture was filtered and the solids washed withdichloromethane (100 mL). The filtrate was added to a cold, stirringsolution of K₂CO₃ (48 g, 347 mmol) in water (480 mL, pH˜10) and stirredfor 10 minutes. The phases were separated and the organic phase washedwith brine (150 mL). The combined aqueous phases were extracted withadditional dichloromethane (100 mL), and the combined organics were thendried, filtered and concentrated in vacuo to provide the product as apale yellow oil (59 g). The oil was crystallized from cold heptane toprovide tert-butyl 2-bromo-6-fluoro-3-(trifluoromethyl)benzoate as anoff-white solid (45 g, 75%). ¹H NMR (400 MHz, DMSO-d₆) δ 8.03 (dd,J=9.0, 5.6 Hz, 1H), 7.68-7.59 (m, 1H), 1.58 (s, 9H) ppm.

Step 3: tert-butyl2-bromo-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoate

tert-Butyl 2-bromo-6-fluoro-3-(trifluoromethyl)benzoate (10 g, 29 mmol)and 3-fluoro-2-methoxy-4-(trifluoromethoxy)phenol (6.8 g, 30 mmol, seeExample 113, Step 1) were dissolved in DMSO (40 mL) and K₂CO₃ (8.1 g,58.6 mmol) (325 mesh) was added under stirring. The yellow suspensionwas heated at 100° C. (internal temperature) for 2 hours. After cooling,the suspension was partitioned between water (200 mL) and 4:1heptane/MTBE (200 mL). The organic phase was washed −20 wt % aqueousK₂CO₃ (2×100 mL), dried, filtered and concentrated in vacuo. Silica gelchromatography (product loaded onto the column with 95:5hexane/dichloromethane; 0-20% ethyl acetate/hexane gradient) providedtert-butyl2-bromo-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoate(13.5 g, 84%). ESI-MS m z calc. 548.01, no ionization observed; LC/MSretention time (Method B): 2.07 minutes. ¹H NMR (400 MHz, DMSO-d₆) δ7.84 (d, J=8.9 Hz, 1H), 7.39 (ddd, J=9.3, 8.1, 1.3 Hz, 1H), 7.15 (dd,J=9.3, 2.2 Hz, 1H), 7.06 (d, J=8.8 Hz, 1H), 3.88 (d, J=1.0 Hz, 3H), 1.52(s, 9H) ppm.

Step 4: tert-butyl6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-3-(trifluoromethyl)benzoate

tert-Butyl2-bromo-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoate(143.8 g, 261.8 mmol) was dissolved in 2-methyltetrahydrofuran (2.2 L)and treated with methylboronic acid (78.5 g, 1.31 mol) and Cs₂CO₃ (256g, 786 mmol) under stirring. The suspension was purged with nitrogen for30 minutes, treated with Pd(dppf)Cl₂ (2.88 g, 3.94 mmol) and heated at80° C. (internal temperature) for 1 hour. The mixture was cooled to roomtemperature and diluted with water (1 L). The phases were separated andthe organic phase washed water (2×1 L) and brine (500 mL). The organicphase was dried, filtered and concentrated in vacuo. The material waspartitioned between 4:1 heptane/MTBE (500 mL) and water and the phasesseparated. The organic phase was washed with water (2×500 mL). Theaqueous phases were back extracted with heptane (200 mL). The combinedorganic phases were stirred with MgSO₄ and charcoal for 30 minutes,filtered over a bed of MgSO₄ and concentrated in vacuo to providetert-butyl6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-3-(trifluoromethyl)benzoate(127 g, 100%). ESI-MS m z calc. 484.11, no ionization observed; LC/MSretention time (Method B): 2.05 minutes. ¹H NMR (400 MHz, DMSO-d₆) δ7.72 (d, J=8.8 Hz, 1H), 7.35 (ddd, J=9.4, 8.1, 1.3 Hz, 1H), 7.00 (dd,J=9.3, 2.2 Hz, 1H), 6.91 (d, J=8.8 Hz, 1H), 3.89 (d, J=0.9 Hz, 3H), 2.41(d, J=1.7 Hz, 3H), 1.49 (s, 9H) ppm.

Step 5:6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-3-(trifluoromethyl)benzoicacid

tert-Butyl6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-3-(trifluoromethyl)benzoate(125 g, 258 mmol) was dissolved in isopropanol (625 mL), treated with 6M aqueous HCl (260 mL, 1.56 mol) and heated at 80-90° C. for 2 hours.The solution was evaporated and azeotroped with isopropanol. The crudematerial was crystallized twice from heptane and once from toluene toprovide6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-3-(trifluoromethyl)benzoicacid (91.8 g, 82%) as a white solid. ESI-MS m z calc. 428.05, found427.0 (M−1)⁻; LC/MS retention time (Method C): 2.14 minutes. ¹H NMR (400MHz, DMSO-d₆) δ 13.80 (s, 1H), 7.69 (d, J=8.9 Hz, 1H), 7.36 (ddd, J=9.4,8.2, 1.3 Hz, 1H), 7.06 (dd, J=9.3, 2.2 Hz, 1H), 6.86 (d, J=8.8 Hz, 1H),3.87 (d, J=1.0 Hz, 3H), 2.43 (d, J=1.7 Hz, 3H) ppm.

Step 6:4-[[6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-3-(trifluoromethyl)benzoyl]amino]-5-methyl-pyridine-2-carboxamide(312)

A solution of6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-3-(trifluoromethyl)benzoicacid (50 mg, 0.12 mmol) and a drop of DMF in dichloromethane (5 mL) wastreated dropwise with oxalyl chloride (89 mg, 61 μL, 0.70 mmol) andstirred at room temperature for 1 hour. The mixture was concentrated invacuo to provide6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-3-(trifluoromethyl)benzoylchloride. The acid chloride was dissolved in NMP (0.5 mL) and added to amixture of methyl 4-amino-5-methyl-pyridine-2-carboxylate (29 mg, 0.18mmol, Preparation 1) and DIEA (143 μL, 0.818 mmol). The mixture wasallowed to stir overnight at 75° C. Purification by reverse phase HPLC(10-99% acetonitrile/5 mM HCl) provided the intermediate methyl4-[[6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-3-(trifluoromethyl)benzoyl]amino]-5-methyl-pyridine-2-carboxylate(36.1 mg, 0.0626 mmol). The material was dissolved in a solution ofammonia in methanol (600 μL of 7 M, 4.2 mmol) and stirred overnightresulting in a slurry. The solid was collected by filtration,re-dissolved in minimal hot methanol, and the resulting clear solutionallowed to slowly cool to room temperature. The resulting solid wascollected by filtration to provide4-[[6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methyl-3-(trifluoromethyl)benzoyl]amino]-5-methyl-pyridine-2-carboxamide(11.2 mg, 32%) as a white solid. ESI-MS m z calc. 561.11, found 562.2(M+1)⁺; LC/MS retention time (Method B): 1.82 minutes. ¹H NMR (400 MHz,DMSO-d₆) δ 10.52 (s, 1H), 8.47 (d, J=6.6 Hz, 2H), 8.06 (d, J=2.8 Hz,1H), 7.75 (d, J=8.9 Hz, 1H), 7.61 (d, J=2.9 Hz, 1H), 7.39 (t, J=8.7 Hz,1H), 7.13 (dd, J=9.3, 2.1 Hz, 1H), 6.89 (d, J=8.8 Hz, 1H), 3.86 (s, 3H),2.29 (s, 3H) ppm.

The compounds set forth in Table 33 were prepared by methods analogousto the preparation of compound 312, Example 122, i.e., amide couplingfollowed by conversion of the ester to the corresponding carboxamide viatreatment with methanolic ammonia, except that compound 317 wassynthesized via a one-step amide coupling with6-aminopyridazine-3-carboxamide

TABLE 33 Additional Compounds Prepared by Methods Analogous to Example122 Cmpd No. Compound Name LC/MS NMR (shifts in ppm) 3132-[[6-[3-fluoro-2-methoxy-4- ESI-MS m/z ¹H NMR (400 MHz, DMSO-d₆) δ(trifluoromethoxy)phenoxy]-2- calc. 547.10, 11.34 (s, 1H), 8.58 (s, 1H),8.45 (d, methyl-3- found 548.0 J = 5.1 Hz, 1H), 8.24 (s, 1H), 7.75-(trifluoromethyl)benzoyl]ami- (M + 1)⁺; LC/MS 7.68 (m, 2H), 7.54 (dd, J= 5.1, 1.6 no]pyridine-4-carboxamide retention time Hz, 1H), 7.37 (t, J= 8.6 Hz, 1H), 7.14 (Method B): (dd, J = 9.3, 2.1 Hz, 1H), 6.86 (d, J =1.81 minutes 8.8 Hz, 1H), 3.84 (s, 3H), 2.44 (d, J = 1.9 Hz, 3H). 3145-[[6-[3-fluoro-2-methoxy-4- ESI-MS m/z ¹H NMR (400 MHz, DMSO-d₆) δ(trifluoromethoxy)phenoxy]-2- calc. 548.09, 11.43 (s, 1H), 9.21 (s, 2H),8.12 (s, methyl-3- found 549.0 1H), 7.77 (d, J = 8.9 Hz, 1H), 7.73 (s,(trifluoromethyl)benzoyl]ami- (M + 1)⁺; LC/MS 1H), 7.38 (ddd, J = 9.4,8.1, 1.4 Hz, no]pyrimidine-2-carboxamide retention time 1H), 7.14 (dd, J= 9.3, 2.1 Hz, 1H), (Method B): 6.90 (d, J = 8.8 Hz, 1H), 3.84 (d, J =1.77 minutes 1.0 Hz, 3H), 2.46 (d, J = 1.8 Hz, 3H). 3156-[[6-[3-fluoro-2-methoxy-4- ESI-MS m/z ¹H NMR (400 MHz, DMSO-d₆) δ(trifluoromethoxy)phenoxy]-2- calc. 548.09, 11.85 (s, 1H), 9.46 (s, 1H),8.95 (s, methyl-3- found 549.0 1H), 8.16 (s, 1H), 7.79-7.70 (m,(trifluoromethyl)benzoyl]ami- (M + 1)⁺; LC/MS 2H), 7.37 (t, J = 8.7 Hz,1H), 7.14 (d, no]pyrimidine-4-carboxamide retention time J = 9.3 Hz,1H), 6.88 (d, J = 8.8 Hz, (Method C): 1H), 3.83 (s, 3H), 2.45 (s, 3H).2.79 minutes 316 5-[[6-[3-fluoro-2-methoxy-4- ESI-MS m/z(trifluoromethoxy)phenoxy]-2- calc. 548.09, methyl-3- found 549.0(trifluoromethyl)benzoyl]ami- (M + 1)⁺; LC/MS no]pyrazine-2-carboxamideretention time (Method C): 2.73 minutes 317 6-[[6-[3-fluoro-2-methoxy-4-ESI-MS m/z ¹H NMR (400 MHz, DMSO-d₆) δ (trifluoromethoxy)phenoxy]-2-calc. 548.09, 12.13 (s, 1H), 8.61 (d, J = 9.3 Hz, methyl-3- found 549.01H), 8.40 (s, 1H), 8.25 (d, J = 9.2 Hz, (trifluoromethyl)benzoyl]ami-(M + 1)⁺; LC/MS 1H), 7.84 (s, 1H), 7.75 (d, J = 8.9 Hz,no]pyridazine-3-carboxamide retention time 1H), 7.37 (t, J = 8.7 Hz,1H), 7.15 (d, (Method B): J = 9.2 Hz, 1H), 6.89 (d, J = 8.8 Hz, 1.93minutes 1H), 3.84 (s, 3H), 2.46 (s, 3H).

Example 1234-[[2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoyl]amino]-5-methyl-pyridine-2-carboxamide(318)

Step 1. methyl2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoate

To a solution of methyl 2,6-difluoro-4-(trifluoromethyl)benzoate (1.000g, 4.164 mmol) in DMF (12 mL) was added3-fluoro-2-methoxy-4-(trifluoromethoxy)phenol (942 mg, 4.17 mmol, seeExample 113, Step 1) and Cs₂CO₃ (4.10 g, 12.6 mmol) and the mixture washeated at 70° C. for 20 minutes. The cooled mixture was diluted withethyl acetate and washed with water and brine. The organic layer wasdried over Na₂SO₄, filtered and concentrated in vacuo. Purification bysilica gel chromatography (0-15% ethyl acetate/hexanes) provided methyl2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoate(1.162 g, 63%). ESI-MS m z calc. 446.04, found 447.2 (M+1)⁺; LC/MSretention time (Method A): 0.83 minutes.

Step 2.2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoicacid

A solution of methyl2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoate(1.16 g, 2.60 mmol) in methanol (8 mL) was treated with aqueous KOH (6mL of 3 M, 18.00 mmol) at 0° C. The cloudy white mixture was allowed tocome to room temperature then heated at 55° C. for 1 hour. The mixturewas partitioned between 1 M aqueous HCl and diethyl ether. The organiclayer was dried over Na₂SO₄, filtered and concentrated in vacuo toprovide a viscous oil. The oil was suspended in hexane and stirred untila thick slurry had formed. The solid was collected by filtration and airdried to provide2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoicacid (745 mg, 66%) as a white solid. ESI-MS m z calc. 432.02, found433.2 (M+1)⁺; LC/MS retention time (Method A): 0.74 minutes. ¹H NMR (400MHz, DMSO-d₆) δ 14.22 (s, 1H), 7.69 (d, J=8.8 Hz, 1H), 7.35 (ddd, J=9.3,8.0, 1.4 Hz, 1H), 7.04 (dd, J=9.4, 2.2 Hz, 1H), 3.88 (s, 4H) ppm.

Step 3:4-[[2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoyl]amino]-5-methyl-pyridine-2-carboxamide(318)

A solution of2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoicacid (25 mg, 0.058 mmol) and DMF (1 μL, 0.01 mmol) in dichloromethane(400 μL) at 0° C. was treated slowly with oxalyl dichloride (30 μL, 0.34mmol). The ice-bath was removed and the mixture was stirred at roomtemperature for 30 minutes. The mixture was concentrated in vacuo. Theresulting acid chloride intermediate was dissolved in NMP (200 μL) andadded dropwise to solution of methyl4-amino-5-methyl-pyridine-2-carboxylate (25 mg, 0.1504 mmol,Preparation 1) and DIEA (60 μL, 0.3445 mmol) in NMP (200 μL) at 0° C.The resulting mixture was stirred at room temperature for 16 hours.Purification by reverse phase HPLC (30-99% acetonitrile/5 mM HCl)provided methyl4-[[2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoyl]amino]-5-methyl-pyridine-2-carboxylate.The material was dissolved in a solution of ammonia in methanol (1.65 mLof 7 M, 11.6 mmol) and stirred at room temperature for 24 hours. Thesolution was concentrated in vacuo and purified by reverse phase HPLC(30-99% acetonitrile/5 mM HCl) to provide4-[[2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoyl]amino]-5-methyl-pyridine-2-carboxamide(7.6 mg, 23%) as a white solid. ESI-MS m z calc. 565.09, found 566.2(M+1)⁺; LC/MS retention time (Method B): 1.27 minutes. ¹H NMR (400 MHz,DMSO-d₆) δ 10.60 (s, 1H), 8.45 (d, J=12.1 Hz, 2H), 8.05 (s, 1H), 7.76(d, J=8.6 Hz, 1H), 7.60 (s, 1H), 7.36 (t, J=8.6 Hz, 1H), 7.25 (s, 1H),7.10 (d, J=9.3 Hz, 1H), 3.89 (s, 3H), 2.27 (s, 3H) ppm.

Example 1244-[[3-(difluoromethyl)-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-2-methoxy-benzoyl]amino]pyridine-2-carboxamide(319)

4-[[4-Chloro-3-(difluoromethyl)-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-2-methoxy-benzoyl]amino]pyridine-2-carboxamide(52.5 mg, 0.090 mmol, see US 2019/0016671, Example 178, which isincorporated by reference) and 10% Pd/C (16 mg) were stirred in methanol(2 mL) under a hydrogen atmosphere (balloon) for 20 minutes. The mixturewas filtered through Celite and concentrated in vacuo. Purification byreverse phase HPLC (47-95% acetonitrile/0.1% ammonium hydroxide)provided4-[[3-(difluoromethyl)-6-[3-fluoro-2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-2-methoxy-benzoyl]amino]pyridine-2-carboxamide(20.2 mg, 38%) ESI-MS m z calc. 548.12, found 549.5 (M+1)⁺; Retentiontime (Method E): 3.22 minutes.

Example 1254-[[2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-4-methoxy-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(320)

Step 1:2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-4-methoxy-3-(trifluoromethyl)benzoicacid

A mixture of 6-bromo-2-fluoro-4-methoxy-3-(trifluoromethyl)benzoic acid(1.5 g, 4.7 mmol, see US 2019/0016671, Example 129, Step 3, which isincorporated by reference),3-fluoro-2-methoxy-4-(trifluoromethoxy)phenol (1.070 g, 4.732 mmol, seeExample 113, Step 1) and Cs₂CO₃ (1.850 g, 5.678 mmol) in toluene (12 mL)was bubbled with nitrogen for 10 minutes, then copper (I) iodide (350mg, 1.84 mmol) added. The mixture was heated at 100° C. under nitrogenwith vigorous stirring for 1 hour. The cooled mixture was acidified with1 M HCl, filtered and the layers separated. The aqueous layer wasextracted with additional ethyl acetate (3×). The combined organiclayers were washed with brine, dried over MgSO₄, filtered andconcentrated in vacuo. Silica gel column chromatography (20-100% ethylacetate/hexane) provided2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-4-methoxy-3-(trifluoromethyl)benzoicacid (1.674 g, 77%). ESI-MS m z calc. 462.04, found 463.2 (M+1)⁺; LC/MSretention time (Method A): 0.71 minutes. ¹H NMR (400 MHz, DMSO-d₆) δ13.76 (s, 1H), 7.33 (t, J=8.7 Hz, 1H), 7.05 (dd, J=9.3, 2.1 Hz, 1H),6.65 (s, 1H), 3.91 (s, 3H), 3.81 (s, 3H) ppm.

Step 2: methyl4-[[2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-4-methoxy-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxylate

2-Fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-4-methoxy-3-(trifluoromethyl)benzoicacid (300 mg, 0.649 mmol) was dissolved in dichloromethane (10 mL) andcooled to 0° C. Oxalyl chloride (150 μL, 1.72 mmol) was added followedby addition of DMF (5 μL, 0.07 mmol). The resulting mixture was stirredfor 1 hour and concentrated in vacuo. The residue was dissolved indichloromethane (10 mL) and methyl 4-aminopyridine-2-carboxylate (99 mg,0.65 mmol) and TEA (200 μL, 1.44 mmol) added. The resulting mixture wasstirred at room temperature overnight, then concentrated in vacuo.Purification by silica gel chromatography (0-100% ethyl acetate/heptane)provided methyl4-[[2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-4-methoxy-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxylate(234 mg, 60%). ESI-MS m z calc. 596.08, found 597.5 (M+1)⁺; 595.6(M−1)⁻; LC/MS retention time (Method F): 1.0 minutes. ¹H NMR (500 MHz,DMSO-d₆) δ 11.33 (s, 1H), 8.61 (d, J=5.3 Hz, 1H), 8.31 (d, J=2.1 Hz,1H), 7.78 (dd, J=5.5, 2.1 Hz, 1H), 7.36-7.28 (m, 1H), 7.13 (dd, J=9.2,2.0 Hz, 1H), 6.69 (s, 1H), 3.92-3.84 (m, 9H) ppm.

Step 3:4-[[2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-4-methoxy-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(320)

A solution of ammonia in methanol (5 mL of 7 M, 35 mmol) was added tomethyl4-[[2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-4-methoxy-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxylate(234 mg, 0.3924 mmol) and the resulting mixture was stirred at roomtemperature overnight. The mixture was concentrated in vacuo to provide4-[[2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-4-methoxy-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(151.9 mg, 64%) as an off-white powder. ESI-MS m z calc. 581.08, found582.5 (M+1)⁺; 580.6 (M−1)⁻; LC/MS retention time (Method E): 3.37minutes. ¹H NMR (500 MHz, DMSO-d₆) δ 11.28 (s, 1H), 8.53 (d, J=5.5 Hz,1H), 8.27 (d, J=2.1 Hz, 1H), 8.08 (d, J=2.9 Hz, 1H), 7.78 (dd, J=5.6,2.2 Hz, 1H), 7.64 (d, J=2.9 Hz, 1H), 7.33 (tt, J=8.0, 1.2 Hz, 1H), 7.14(dd, J=9.3, 2.1 Hz, 1H), 6.67 (s, 1H), 3.89-3.84 (m, 6H) ppm.

Example 1265-[[2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-4-methoxy-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(321)

This compound was made in an analogous fashion to the synthesis ofcompound 320 in Example 125, except employing5-aminopyridine-2-carboxamide in the amide formation step. The yield5-[[2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-4-methoxy-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamideafter purification was 171 mg (44%). ESI-MS m z calc. 581.08, found582.5 (M+1)⁺; 580.6 (M−1)⁻; LC/MS retention time (Method E): 3.32minutes. 1H NMR (500 MHz, DMSO-d₆) δ 11.21 (s, 1H), 8.80 (d, J=2.4 Hz,1H), 8.22 (dd, J=8.6, 2.5 Hz, 1H), 8.06-7.98 (m, 2H), 7.55 (d, J=2.9 Hz,1H), 7.33 (ddd, J=9.4, 8.1, 1.4 Hz, 1H), 7.14 (dd, J=9.3, 2.1 Hz, 1H),6.70 (s, 1H), 3.94-3.80 (m, 6H) ppm.

Example 1274-[[2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethoxy)benzoyl]amino]pyridine-2-carboxamide(322)

Step 1:2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethoxy)benzoicacid

A mixture of 6-bromo-2-fluoro-3-(trifluoromethoxy)benzoic acid (966 mg,3.19 mmol, see Example 90, Step 1),3-fluoro-2-methoxy-4-(trifluoromethoxy)phenol (750 mg, 3.32 mmol, seeExample 113, Step 1) and Cs₂CO₃ (1.2 g, 3.7 mmol) in toluene (15 mL) wastreated with copper (I) iodide (230 mg, 1.21 mmol) and the mixtureheated at 100° C. with vigorous stirring overnight. The mixture is thenacidified with 2 M aqueous HCl, filtered and the layers separated. Theaqueous layer was extracted with ethyl acetate, and the combined aqueouslayers washed with brine, dried over MgSO₄, filtered and concentrated invacuo to provide crude2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethoxy)benzoicacid (1.5 g, 105%). ESI-MS m z calc. 448.02, no ionization observed;LC/MS retention time (Method F): 0.63 minutes. ¹H NMR (400 MHz, CDCl₃) δ9.63 (s, 1H), 7.36 (ddq, J=9.3, 8.2, 1.1 Hz, 1H), 7.08 (ddq, J=9.0, 7.7,1.3 Hz, 1H), 6.98-6.81 (m, 1H), 6.59 (dd, J=9.2, 1.9 Hz, 1H), 3.96 (d,J=1.5 Hz, 3H) ppm. This material was used without further purification.

Step 2:4-[[2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethoxy)benzoyl]amino]pyridine-2-carboxamide(322)

A solution of2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethoxy)benzoicacid (300 mg, 0.669 mmol) and DMF (5 μL, 0.07 mmol) in dichloromethane(5 mL) at 0° C. was treated dropwise with oxalyl chloride (235 μL, 2.69mmol) (gas evolution) and stirred for 1 hour. The mixture wasconcentrated in vacuo, and the resulting acid chloride dissolved indichloromethane (5 mL) and added dropwise to a stirring solution ofmethyl 4-aminopyridine-2-carboxylate (112 mg, 0.736 mmol), DIPEA (350μL, 2.01 mmol) and DMAP (82 mg, 0.67 mmol) in dichloromethane (5 mL).The mixture was stirred overnight, concentrated in vacuo, and theresidue stirred in a solution of ammonia in methanol (5.0 mL of 7 M, 35mmol) for 24 hours. The mixture was concentrated in vacuo and purifiedby reverse phase HPLC (47-95% acetonitrile/0.1% ammonium hydroxide) toprovide4-[[2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethoxy)benzoyl]amino]pyridine-2-carboxamide(112 mg, 28% yield). ESI-MS m z calc. 567.07, found 568.1 (M+1)⁺; 566.1(M−1)⁻; LC/MS retention time (Method F): 0.95 minutes. ¹H NMR (400 MHz,CDCl₃) δ 9.82 (s, 1H), 8.55 (d, J=5.5 Hz, 1H), 8.49 (dd, J=5.7, 2.0 Hz,1H), 8.19 (d, J=2.2 Hz, 1H), 7.91 (d, J=4.3 Hz, 1H), 7.37 (tq, J=8.2,1.2 Hz, 1H), 7.13-6.92 (m, 2H), 6.60 (ddd, J=20.3, 9.2, 1.8 Hz, 1H),5.23 (d, J=4.5 Hz, 1H), 3.89 (d, J=1.8 Hz, 3H) ppm.

Example 1284-[[2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-3-methyl-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(323)

Step 1:2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-3-methyl-4-(trifluoromethyl)benzoicacid

A solution of n-butyllithium (760 μL of 1.6 M in hexanes, 1.22 mmol) wasadded to a stirring solution of diisopropylamine (121 mg, 1.20 mmol) inTHF (5 mL) at −78° C. and the mixture stirred at 0° C. for 20 minutes.The resulting LDA solution was added dropwise to a solution methyl2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoate(450 mg, 1.01 mmol, see Example 123, Step 1) in THF (5 mL) at −78° C.The mixture was stirred at this temperature for 20 minutes then methyliodide (232 mg, 1.64 mmol) was added. The mixture was stirred at −78° C.for 30 minutes then allowed to warm to room temperature and stirredovernight. The mixture was diluted with water and extracted with ethylacetate (3×). The combined organic extracts were dried over MgSO₄,filtered and concentrated in vacuo to provide methyl2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-3-methyl-4-(trifluoromethyl)benzoate.The residue was taken up in ethanol (5 mL), treated with aqueous LiOH (3mL of 2 M, 6 mmol) and stirred overnight. The mixture was acidified with2 M aqueous HCl and extracted with ethyl acetate (2×30 mL). The combinedorganic extracts were dried over MgSO₄, filtered and then concentratedin vacuo to provide2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-3-methyl-4-(trifluoromethyl)benzoicacid (350 mg, 78%). ESI-MS m z calc. 446.04, found 445.1 (M−1)⁻; LC/MSretention time (Method F): 0.65 minutes.

Step 2:4-[[2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-3-methyl-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(323)

To a solution of2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-3-methyl-4-(trifluoromethyl)benzoicacid (460 mg, 1.03 mmol) and DMF (8 μL, 0.1 mmol) in dichloromethane (10mL) at 0° C. was added oxalyl chloride (1.6 mL of 2 M, 3.2 mmol)dropwise. The mixture was stirred for 2 hours and concentrated in vacuo.The residue was dissolved in dichloromethane (10 mL) and added dropwiseto a mixture of methyl 4-aminopyridine-2-carboxylate (220 mg, 1.45 mmol)and TEA (9 μL, 0.06 mmol) in dichloromethane (10 mL) at 0° C. Theresulting mixture was allowed to warm to room temperature overnight,then concentrated in vacuo. Purification by reverse phase HPLC (47-95%acetonitrile/0.1% ammonium hydroxide) provided methyl4-[[2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-3-methyl-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxylate.The material was dissolved in a solution of ammonia in methanol (2 mL of7 M, 14 mmol) and stirred overnight at room temperature. The mixture wasconcentrated in vacuo to provide4-[[2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-3-methyl-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(58.5 mg, 10%). ESI-MS m z calc. 565.09, found 566.1 (M+1)⁺; 564.2(M−1)⁻; LC/MS retention time (Method F): 0.98 minutes. ¹H NMR (400 MHz,CDCl₃) δ 9.53 (s, 1H), 8.55 (d, J=5.5 Hz, 1H), 8.43 (dd, J=5.6, 2.1 Hz,1H), 8.14 (d, J=2.1 Hz, 1H), 7.90 (d, J=4.2 Hz, 1H), 7.07 (ddq, J=8.9,7.6, 1.2 Hz, 1H), 6.97 (dd, J=9.2, 2.1 Hz, 1H), 6.89 (d, J=1.4 Hz, 1H),5.23 (d, J=4.3 Hz, 1H), 3.88 (d, J=1.8 Hz, 3H), 2.41 (p, J=1.8 Hz, 3H)ppm.

Example 1294-[[3-chloro-2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-4-methoxy-benzoyl]amino]pyridine-2-carboxamide(324)

Step 1:3-chloro-2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-4-methoxy-benzoicacid

A solution of 3-fluoro-2-methoxy-4-(trifluoromethoxy)phenol (2.001 g,8.849 mmol, see Example 113, Step 1) in toluene (50 mL) was bubbled withnitrogen for 10 minutes. 6-Bromo-3-chloro-2-fluoro-4-methoxy-benzoicacid (2.5 g, 8.8 mmol, see Example 76, Step 2), copper (I) iodide (338mg, 1.78 mmol) and Cs₂CO₃ (5.749 g, 17.64 mmol) were added and themixture was bubbled with nitrogen for 10 minutes. The mixture was heatedto 100° C. for 21 hours. The cooled mixture was diluted with ethylacetate (175 mL) and washed with saturated aqueous NH₄Cl (175 mL). Theaqueous layer was extracted with additional ethyl acetate (2×100 mL),and the combined organic extracts dried over MgSO₄, filtered andconcentrated in vacuo. Purification by silica gel chromatography (0-50%ethyl acetate/heptane) provided3-chloro-2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-4-methoxy-benzoicacid (1.789 g, 47%). ESI-MS m z calc. 428.01, found 429.5 (M+1)⁺; LC/MSretention time (Method F): 0.59 minutes. ¹H NMR (500 MHz, DMSO-d₆) δ13.60 (s, 1H), 7.25 (t, J=8.5 Hz, 1H), 6.83 (m, 2H), 3.93 (s, 3H), 3.84(s, 3H) ppm.

Step 2: methyl4-[[3-chloro-2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-4-methoxy-benzoyl]amino]pyridine-2-carboxylate

To a solution of3-chloro-2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-4-methoxy-benzoicacid (250 mg, 0.583 mmol) in dichloromethane (5 mL) and DMF (5 μL, 0.07mmol) at 0° C. was added oxalyl chloride (150 μL, 1.72 mmol). Themixture was warmed to room temperature, stirred for 30 minutes, thenconcentrated in vacuo. The residue was dissolved in dichloromethane (2.5mL) and added to a solution of methyl 4-aminopyridine-2-carboxylate (110mg, 0.723 mmol) and TEA (250 μL, 1.79 mmol) in dichloromethane (2.5 mL)at 0° C. The mixture was warmed to room temperature and stirred for 1hour. The mixture was diluted with dichloromethane (20 mL) and washedwith water (30 mL). The aqueous layer was extracted with additionaldichloromethane (2×20 mL), and the combined organic extracts dried overMgSO₄, filtered and concentrated in vacuo. Purification by silica gelchromatography (0-80% ethyl acetate/heptane) provided methyl4-[[3-chloro-2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-4-methoxy-benzoyl]amino]pyridine-2-carboxylate(164 mg, 50%). ESI-MS m z calc. 562.06, found 563.4 (M+1)⁺; 561.6(M−1)⁻; LC/MS retention time (Method F): 0.94 minutes. ¹H NMR (500 MHz,DMSO-d₆) δ 11.28 (s, 1H), 8.59 (d, J=5.4 Hz, 1H), 8.28 (d, J=2.1 Hz,1H), 7.75 (dd, J=5.5, 2.1 Hz, 1H), 7.29-7.22 (m, 1H), 6.97 (dd, J=9.4,2.1 Hz, 1H), 6.81 (d, J=1.9 Hz, 1H), 3.87 (s, 6H), 3.85 (d, J=0.8 Hz,3H) ppm.

Step 3:4-[[3-chloro-2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-4-methoxy-benzoyl]amino]pyridine-2-carboxamide(325)

Methyl4-[[3-chloro-2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-4-methoxy-benzoyl]amino]pyridine-2-carboxylate(160 mg, 0.284 mmol) was dissolved in a solution of ammonia in methanol(1.5 mL of 7 M, 10.5 mmol) and stirred at room temperature for 68 hours.The mixture was concentrated in vacuo. The residue was partitionedbetween dichloromethane (20 mL) and water (20 mL) and the layersseparated. The aqueous layer was extracted with additionaldichloromethane (2×20 mL), and the combined organic extracts dried overMgSO₄, filtered and concentrated in vacuo to provide4-[[3-chloro-2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-4-methoxy-benzoyl]amino]pyridine-2-carboxamide(57.9 mg, 35%). ESI-MS m z calc. 547.06, found 548.4 (M+1)⁺; 546.4(M−1)⁻; LC/MS retention time (Method E): 3.21 minutes. ¹H NMR (500 MHz,DMSO-d₆) δ 11.23 (s, 1H), 8.51 (d, J=5.4 Hz, 1H), 8.23 (d, J=2.1 Hz,1H), 8.07 (d, J=2.8 Hz, 1H), 7.75 (dd, J=5.6, 2.2 Hz, 1H), 7.63 (d,J=2.8 Hz, 1H), 7.26 (ddd, J=9.3, 8.1, 1.3 Hz, 1H), 6.97 (dd, J=9.4, 2.1Hz, 1H), 6.80 (d, J=1.6 Hz, 1H), 3.87 (s, 3H), 3.86 (s, 3H) ppm.

Example 1304-[[2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-3-methoxy-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(325)

Step 1:2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-3-methoxy-4-(trifluoromethyl)benzoicacid

A mixture of 2-fluoro-6-iodo-3-methoxy-4-(trifluoromethyl)benzoic acid(750 mg, 1.65 mmol, see Example 94, Step 4),3-fluoro-2-methoxy-4-(trifluoromethoxy)phenol (516 mg, 2.28 mmol, seeExample 113, Step 1) and Cs₂CO₃ (1.086 g, 3.333 mmol) in toluene (15 mL)was bubbled with nitrogen for 10 minutes. Copper (I) iodide (63.4 mg,0.333 mmol) was added and the mixture heated at 100° C. under nitrogenfor 20 hours. The cooled mixture was partitioned between water (100 ml)and ethyl acetate (100 mL) and acidified to pH=3 with 2 M aqueous HCl.The mixture was extracted with ethyl acetate (4×75 mL), and the combinedorganic extracts washed with water (100 mL), dried over MgSO₄, filteredand concentrated in vacuo. Purification using silica gel chromatography(0-30% ethyl acetate/heptane) provided2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-3-methoxy-4-(trifluoromethyl)benzoicacid (240 mg, 27%). ESI-MS m z calc. 462.03, found 461.4 (M−1)⁻; LC/MSretention time (Method F): 0.63 minutes.

Step 2:4-[[2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-3-methoxy-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(325)

To a solution of2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-3-methoxy-4-(trifluoromethyl)benzoicacid (75 mg, 0.14 mmol) in dichloromethane (2 mL) and DMF (1 μL, 0.01mmol) at 0° C. was added oxalyl chloride (40 μL, 0.46 mmol). The mixturewas warmed to room temperature, stirred for 30 minutes and thenconcentrated in vacuo. The residue was dissolved in dichloromethane (1mL) and added to a solution of methyl 4-aminopyridine-2-carboxylate(23.4 mg, 0.154 mmol) and TEA (60 μL, 0.43 mmol) in dichloromethane (1mL) at 0° C. The mixture was warmed to room temperature and stirred for20 hours. The mixture was diluted with dichloromethane (20 mL) andwashed with water (20 mL). The aqueous layer was extracted withadditional dichloromethane (2×20 mL), and the combined organic extractswere dried over MgSO₄, filtered and concentrated in vacuo. The residuewas dissolved in a solution of ammonia in methanol (1 mL of 7 M, 7 mmol)and stirred for 20 hours. The mixture was concentrated in vacuo andpurified by reverse phase HPLC (47-95% acetonitrile/0.1% ammoniumhydroxide) to provide4-[[2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-3-methoxy-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(17 mg, 21%). ESI-MS m z calc. 581.08, found 582.4 (M+1)⁺; 580.4 (M−1)⁻;LC/MS retention time (Method F): 3.44 minutes. ¹H NMR (500 MHz, DMSO-d₆)δ 11.44 (s, 1H), 8.54 (d, J=5.5 Hz, 1H), 8.26 (d, J=2.2 Hz, 1H), 8.09(d, J=2.8 Hz, 1H), 7.75 (dd, J=5.4, 2.2 Hz, 1H), 7.65 (d, J=2.8 Hz, 1H),7.30 (ddd, J=9.6, 8.2, 1.2 Hz, 1H), 7.23 (d, J=1.5 Hz, 1H), 7.01 (dd,J=9.3, 2.2 Hz, 1H), 4.00 (d, J=1.3 Hz, 3H), 3.85 (d, J=0.8 Hz, 3H) ppm.

Example 1314-[[4-chloro-2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-3-methoxy-benzoyl]amino]pyridine-2-carboxamide(326)

Step 1: 6-bromo-4-chloro-2-fluoro-3-methoxy-benzoic acid

To a solution of 5-bromo-1-chloro-3-fluoro-2-methoxy-benzene (2.8 g,11.7 mmol) in THF (20 mL) was added a solution of LDA (7 mL of 2 M inTHF/heptane/ethylbenzene, 14 mmol) dropwise while maintaining thetemperature below −65° C. The mixture was stirred at −70° C. for 30minutes then poured onto solid carbon dioxide (dry ice) and stirreduntil at room temperature and no more effervescence was observed. Themixture was partitioned between water (20 mL) and ethyl acetate (20 mL)and the layers separated. The aqueous layer was acidified to pH=3 byaddition of 1 M aqueous HCl and then extracted with ethyl acetate (3×30mL). The combined extracts were dried over MgSO₄, filtered andconcentrated in vacuo to provide6-bromo-4-chloro-2-fluoro-3-methoxy-benzoic acid (2.6 g, 78%). ¹H NMR(500 MHz, DMSO-d₆) δ 14.39 (s, 1H), 7.77 (d, J=2.0 Hz, 1H), 3.92 (d,J=1.4 Hz, 3H) ppm

Step 2:4-chloro-2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-3-methoxy-benzoicacid

A mixture of 6-bromo-4-chloro-2-fluoro-3-methoxy-benzoic acid (800 mg,2.82 mmol), 3-fluoro-2-methoxy-4-(trifluoromethoxy)phenol (700 mg, 3.10mmol, see Example 113, Step 1), copper (I) iodide (110 mg, 0.578 mmol)and Cs₂CO₃ (1.84 g, 5.65 mmol) in toluene (25 mL) was heated at 100° C.overnight. The cooled mixture was diluted with water and ethyl acetate(50 mL), then acidified with 2 M aqueous HCl (30 mL). The ethyl acetatelayer was washed with water, then dried over Na₂SO₄, filtered andconcentrated in vacuo to provide4-chloro-2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-3-methoxy-benzoicacid (870 mg, 72%). ESI-MS m z calc. 428.01, found 427.1 (M−1)⁻; LC/MSretention time (Method F): 0.58 minutes.

Step 3:4-[[4-chloro-2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-3-methoxy-benzoyl]amino]pyridine-2-carboxamide(326)

A solution of4-chloro-2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-3-methoxy-benzoicacid (220 mg, 0.513 mmol) in dichloromethane (3 mL) at 0° C. was treatedwith DMF (40 μL, 0.52 mmol) followed by the dropwise addition of oxalylchloride (180 μL, 2.06 mmol) (gas evolution). The mixture was stirredfor 1 hour, and then concentrated in vacuo. The residue was dissolved indichloromethane (3 mL) and added dropwise to a stirring solution ofmethyl 4-aminopyridine-2-carboxylate (91 mg, 0.57 mmol), DIPEA (280 μL,1.61 mmol) and DMAP (64 mg, 0.52 mmol) in dichloromethane (3 mL). Themixture was stirred overnight then concentrated in vacuo. The residuewas treated with excess ammonia (7 M in methanol) and stirred for threedays at room temperature. Purification by reverse phase HPLC (47-95%acetonitrile/0.1% ammonium hydroxide) provided4-[[4-chloro-2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-3-methoxy-benzoyl]amino]pyridine-2-carboxamide(26.6 mg, 9%). ESI-MS m z calc. 547.06, found 548.1 (M+1)⁺; 546.1(M−1)⁻; LC/MS retention time (Method F): 0.94 minutes. ¹H NMR (400 MHz,CDCl₃) δ 9.54 (s, 1H), 8.54 (d, J=5.5 Hz, 1H), 8.43 (dd, J=5.6, 2.1 Hz,1H), 8.15-8.09 (m, 1H), 7.91 (d, J=4.5 Hz, 1H), 7.06 (ddq, J=8.9, 7.6,1.2 Hz, 1H), 6.96 (dd, J=9.2, 2.1 Hz, 1H), 6.66 (d, J=2.0 Hz, 1H), 5.47(d, J=4.4 Hz, 1H), 3.99 (d, J=1.0 Hz, 3H), 3.91 (d, J=1.8 Hz, 3H) ppm.

Example 1324-[[2,2-difluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-4-methyl-1,3-benzodioxole-5-carbonyl]amino]pyridine-2-carboxamide(327)

Step 1: 2,2-difluoro-4-methyl-1,3-benzodioxole-5-carboxylic acid

To a solution of 2,2-difluoro-1,3-benzodioxole-5-carboxylic acid (0.10g, 0.49 mmol) in THF (7.0 mL) cooled to −78° C. was added n-butyllithium(0.5 mL of 2 M, 1 mmol). The mixture was allowed to warm to 4° C. andstirred for 4 hours, and then cooled to −78° C. and methyl iodide (160mg, 0.07 mL, 1.1 mmol) added. The mixture was allowed to warm to 4° C.and stirred for 4 hours, and then allowed to warm to room temperatureand stirred overnight. The mixture was diluted with 1 M aqueous HCl andthe volatiles removed under reduced pressure. The resulting aqueousmixture was extracted with ethyl acetate. The organic phase was washedwith water and concentrated in vacuo to provide2,2-difluoro-4-methyl-1,3-benzodioxole-5-carboxylic acid (100 mg, 79%)as a pale yellow solid. ESI-MS m z calc. 216.02, no ionization observed;LC/MS retention time (Method S): 2.64 minutes. ¹H NMR (250 MHz, CDCl₃) δ7.96 (d, J=8.7 Hz, 1H), 6.99 (d, J=8.5 Hz, 1H), 2.61 (s, 3H) ppm.

Step 2: 2,2-difluoro-4-methyl-6-nitro-1,3-benzodioxole-5-carboxylic acid

A solution of 2,2-difluoro-4-methyl-1,3-benzodioxole-5-carboxylic acid(0.50 g, 2.1 mmol) in fuming HNO₃ (11 mL) was stirred at roomtemperature overnight. The mixture was diluted with ethyl acetate andwater while cooling in ice bath. The layers were separated, and theorganic phase was washed with water (2×) and concentrated in vacuo toprovide 2,2-difluoro-4-methyl-6-nitro-1,3-benzodioxole-5-carboxylic acid(0.59 g, 98%). ESI-MS m z calc. 261.01, no ionization observed; LC/MSretention time (Method S): 2.48 minutes. H NMR (250 MHz, CDCl₃) δ 7.81(s, 1H), 2.47 (s, 3H) ppm.

Step 3: 6-amino-2,2-difluoro-4-methyl-1,3-benzodioxole-5-carboxylic acid

To a solution of2,2-difluoro-4-methyl-6-nitro-1,3-benzodioxole-5-carboxylic acid (0.70g, 2.4 mmol) in ethyl acetate (35 mL), water (35 mL) and acetic acid(1.9 g, 1.8 mL, 32 mmol) was added Fe (500 mg, 8.95 mmol). The mixturewas stirred at 80° C. for 2 hours. The cooled mixture was basified to pH7-8 with NaHCO₃ and filtered. The layers were separated and the organicphase was washed with brine, dried over MgSO₄, filtered and concentratedto provide 6-amino-2,2-difluoro-4-methyl-1,3-benzodioxole-5-carboxylicacid (0.685 g, 98%) as a dark brown solid. ESI-MS m z calc. 231.03,found 232.0 (M+1)⁺; LC/MS retention time (Method S): 2.5 minutes.

Step 4: 6-bromo-2,2-difluoro-4-methyl-1,3-benzodioxole-5-carboxylic acid

To a solution of6-amino-2,2-difluoro-4-methyl-1,3-benzodioxole-5-carboxylic acid (100mg, 0.346 mmol) in acetonitrile (2 mL) at 0° C. was added tert-butylnitrite (60 mg, 0.07 mL, 0.58 mmol). The mixture was stirred at 4° C.for 15 minutes, then copper (II) bromide (130 mg, 0.582 mmol) added. Themixture was allowed to warm to room temperature and stirred for 3 hours.The mixture was diluted with ethyl acetate/hexanes and water, and thenfiltered. The layers were separated and the organic phase was washedwith brine, dried over MgSO₄ and concentrated to provide6-bromo-2,2-difluoro-4-methyl-1,3-benzodioxole-5-carboxylic acid (95 mg,65%) as a brown solid. ESI-MS m z calc. 293.93, no ionization observed;LC/MS retention time (Method S): 2.67 minutes.

Step 5:2,2-difluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-4-methyl-1,3-benzodioxole-5-carboxylicacid

A mixture of 6-bromo-2,2-difluoro-4-methyl-1,3-benzodioxole-5-carboxylicacid (514 mg, 1.74 mmol) in toluene (12 mL) was flushed with nitrogenfor 10 minutes. 3-Fluoro-2-methoxy-4-(trifluoromethoxy)phenol (604 mg,2.67 mmol, see Example 113, Step 1) and Cs₂CO₃ (1.24 g, 3.806 mmol) wereadded to the mixture and flushed with nitrogen. Copper (I) iodide (106mg, 0.558 mmol) was added to the mixture and flushed with nitrogen for10 minutes. The mixture was heated at 100° C. with vigorous stirring for20 hours under nitrogen. The cooled mixture was diluted with ethylacetate, water and acidified with 1 M aqueous HCl. The layers wereseparated and the aqueous layer extracted with additional ethyl acetate(3×). The combined organic extracts were filtered, and the layersseparated. The organic phase was washed with water and brine, dried overNa₂SO₄, filtered through Celite and concentrated. The residue waspurified by reverse phase HPLC (1-99% acetonitrile/5 mM HCl) to provide2,2-difluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-4-methyl-1,3-benzodioxole-5-carboxylicacid (204.7 mg, 27%) as an off white solid. ESI-MS m z calc. 440.03,found 441.3 (M+1)⁺; LC/MS retention time (Method C): 2.8 minutes.

Step 6:4-[[2,2-difluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-4-methyl-1,3-benzodioxole-5-carbonyl]amino]pyridine-2-carboxamide(327)

To a solution of2,2-difluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-4-methyl-1,3-benzodioxole-5-carboxylicacid (32.6 mg, 0.0741 mmol) and DMF (15 μL, 0.19 mmol) indichloromethane (1 mL) at 0° C. was added oxalyl chloride (30 μL, 0.34mmol) dropwise under nitrogen. The ice bath was removed after 10 minutesand the mixture was stirred at room temperature for 1 hour. The mixturewas concentrated in vacuo to afford2,2-difluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-4-methyl-1,3-benzodioxole-5-carbonylchloride. The acid chloride was dissolved in 2-MeTHF (500 μL) and addedslowly to a mixture of 4-aminopyridine-2-carboxamide (13 mg, 0.095 mmol)and DIEA (32 μL, 0.18 mmol) in 2-MeTHF (500 μL) at 0° C. The suspensionwas stirred at 75° C. for 17 hours. The mixture was concentrated invacuo and purified by reverse phase HPLC (1-99% acetonitrile/5 mM HCl)to provide4-[[2,2-difluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-4-methyl-1,3-benzodioxole-5-carbonyl]amino]pyridine-2-carboxamide(14.0 mg, 34%) as a white solid. ESI-MS m z calc. 559.08, found 560.2(M+1)⁺; LC/MS retention time (Method C): 2.7 minutes. ¹H NMR (400 MHz,DMSO-d₆) δ 11.17 (s, 1H), 8.51 (d, J=5.5 Hz, 1H), 8.29 (d, J=2.1 Hz,1H), 8.08 (d, J=2.8 Hz, 1H), 7.77 (dd, J=5.5, 2.2 Hz, 1H), 7.64 (d,J=2.8 Hz, 1H), 7.32-7.22 (m, 2H), 6.93 (dd, J=9.4, 2.1 Hz, 1H), 3.81 (s,3H), 2.31 (s, 3H) ppm.

Example 1334-[[2,2,4-trifluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-1,3-benzodioxole-5-carbonyl]amino]pyridine-2-carboxamide(328)

Step 1: 2,2,4-trifluoro-1,3-benzodioxole-5-carboxylic acid

To a solution of 2,2-difluoro-1,3-benzodioxole-5-carboxylic acid (200mg, 0.990 mmol) in anhydrous THF (5 mL) was added n-butyllithium (1 mLof 2.5 M in hexane, 2.5 mmol) dropwise at −78° C. The mixture wasstirred at the same temperature for 10 minutes and then warmed to 0° C.and stirred for 1 hour. The mixture was cooled to −78° C. and treateddropwise with a solution N-(benzenesulfonyl)-N-fluoro-benzenesulfonamide(939 mg, 2.98 mmol) in anhydrous THF (5 mL). The mixture was warmed toroom temperature and diluted with water (10 mL). The volatiles wereremoved in vacuo and 2 N Na₂CO₃ solution added to adjust the pH to 10.The aqueous solution was washed with diethyl ether (20 mL), and thenacidified with 1 M aqueous HCl to pH 2. The solution was extracted withethyl acetate (3×25 mL), and the combined organic extracts were washedwith brine (25 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by silica gelchromatography (0-10% methanol/dichloromethane containing 0.3% aceticacid) to provide 2,2,4-trifluoro-1,3-benzodioxole-5-carboxylic acid (114mg, 52%) as an off-white solid. ESI-MS m z calc. 220.00, found 220.7(M+1)⁺; LC/MS retention time (Method N): 3.96 minutes. ¹H NMR (250 MHz,dimethyl sulfoxide-d₆) δ 7.79 (dd, J=8.4, 6.9 Hz, 1H), 7.39 (d, J=8.7Hz, 1H) ppm.

Step 2: 2,2,4-trifluoro-6-iodo-1,3-benzodioxole-5-carboxylic acid

A mixture of 2,2,4-trifluoro-1,3-benzodioxole-5-carboxylic acid (2.588g, 10.58 mmol), iodobenzene diacetate (7.046 g, 21.88 mmol), iodine(5.412 g, 21.32 mmol) and Pd(OAc)₂ (266 mg, 1.19 mmol) in DMF (50 mL)was stirred at 60° C. for 24 hours. The mixture was diluted with water(50 mL) and adjusted to pH=12 with 1 M aqueous NaOH. The aqueoussolution was diluted with diethyl ether (50 mL) and the biphasic mixturefiltered through Celite to remove the solids. The layers were separated,and the aqueous layer washed with additional diethyl ether (50 mL). Theaqueous layer was acidified with 1 M aqueous HCl to pH=2 and extractedwith ethyl acetate (3×100 mL). The combined organic extracts were washedwith saturated aqueous Na₂S₂O₃ (100 mL) and brine (3×100 mL), dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo. Purification bysilica gel chromatography (0-20% methanol/dichloromethane containing0.3% acetic acid) was followed by reverse phase HPLC purification(0-100% acetonitrile/water containing 0.1% TFA). The volatiles from theHPLC purification were removed in vacuo, and the remaining aqueoussolution extracted with ethyl acetate (4×100 mL). The combined organicextracts were washed with brine (100 mL), dried over anhydrous Na₂SO₄,filtered and concentrated in vacuo to provide2,2,4-trifluoro-6-iodo-1,3-benzodioxole-5-carboxylic acid (2.33 g, 64%)as a white solid. ESI-MS m z calc. 345.90, found 347.0 (M+1)⁺; LC/MSretention time (Method N): 4.47 minutes. ¹H NMR (250 MHz, DMSO-d₆) δ7.92 (s, 1H) ppm.

Step 3:2,2,4-trifluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-1,3-benzodioxole-5-carboxylicacid

A pressure vessel containing2,2,4-trifluoro-6-iodo-1,3-benzodioxole-5-carboxylic acid (801 mg, 2.31mmol) and toluene (17.5 mL) was flushed with nitrogen for 10 minutes.3-Fluoro-2-methoxy-4-(trifluoromethoxy)phenol (1.024 g, 4.528 mmol, seeExample 113, Step 1) and Cs₂CO₃ (1.771 g, 5.436 mmol) were added to themixture and flushed with nitrogen for 10 minutes. Copper (I) iodide (461mg, 2.42 mmol) was added to the mixture and flushed with nitrogen for 10min. The mixture was heated at 100° C. with vigorous stirring for 5hours. The cooled mixture was diluted with ethyl acetate and water, andthen acidified with 1 M aqueous HCl. The layers were separated and theaqueous layer was extracted with additional ethyl acetate (3×). Thecombined organic extracts were washed with water and brine, dried overNa₂SO₄, filtered through Celite and concentrated. Purification byreverse phase HPLC (1-99% acetonitrile/5 mM HCl) provided2,2,4-trifluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-1,3-benzodioxole-5-carboxylicacid (321.9 mg, 31%). ESI-MS m z calc. 444.01, found 445.09 (M+1)⁺;LC/MS retention time (Method C): 2.76 minutes. ¹H NMR (400 MHz, DMSO-d₆)δ 13.99 (s, 1H), 7.42-7.19 (m, 2H), 6.91 (dd, J=9.3, 2.1 Hz, 1H), 3.91(s, 3H) ppm.

Step 4:4-[[2,2,4-trifluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-1,3-benzodioxole-5-carbonyl]amino]pyridine-2-carboxamide(328)

To a solution of2,2,4-trifluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-1,3-benzodioxole-5-carboxylicacid (70 mg, 0.16 mmol) and DMF (15 μL, 0.19 mmol) in dichloromethane (2mL) at 0° C. was added oxalyl chloride (41 μL, 0.47 mmol) dropwise undernitrogen. The ice bath was removed after 10 minutes and the mixture wasstirred at room temperature for 1 hour. The mixture was concentrated invacuo to afford2,2,4-trifluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-1,3-benzodioxole-5-carbonylchloride. The acid chloride was suspended in 2-MeTHF (1 mL), cooled to0° C., and treated with a mixture of 4-aminopyridine-2-carboxamide (34.1mg, 0.249 mmol) and DIEA (72 μL, 0.41 mmol) in 2-MeTHF (1 mL) cooled to0° C. The resulting mixture was stirred at 75° C. for 21 hours. Themixture was concentrated in vacuo and purified using reverse phase HPLC(1-99% acetonitrile/5 mM HCl) to provide4-[[2,2,4-trifluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-1,3-benzodioxole-5-carbonyl]amino]pyridine-2-carboxamide(19.5 mg, 21%). ESI-MS m z calc. 563.06, found 564.1 (M+1)⁺; LC/MSretention time (Method C): 2.79 minutes. ¹H NMR (400 MHz, DMSO-d₆) δ11.38 (s, 1H), 8.54 (d, J=5.4 Hz, 1H), 8.27 (d, J=2.1 Hz, 1H), 8.10 (d,J=2.7 Hz, 1H), 7.77 (dd, J=5.5, 2.2 Hz, 1H), 7.66 (d, J=2.8 Hz, 1H),7.43-7.14 (m, 2H), 7.03 (dd, J=9.3, 2.1 Hz, 1H), 3.84 (s, 3H) ppm.

Example 1346-[[2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyrimidine-4-carboxamide(329)

Step 1:2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoicacid

A mixture of 6-bromo-2-fluoro-3-(trifluoromethyl)benzoic acid (35.0 g,122 mmol), 3-fluoro-2-methoxy-4-(trifluoromethoxy)phenol (27.6 g, 122mmol, see Example 113, Step 1) and Cs₂CO₃ (79.5 g, 244 mmol) in degassedtoluene (657 mL, bubbled with nitrogen for 20 minutes) was stirred for10 minutes. Copper (I) iodide (4.65 g, 24.4 mmol) was added and themixture heated at 100° C. for 1 hour. The mixture was cooled to roomtemperature and diluted with MTBE (350 mL). The solution was washed with4 M aqueous NH₄Cl (4×200 mL), 1 M aqueous HCl (183 mL) and brine (125mL). The organic layer was dried over MgSO₄ and concentrated in vacuo toprovide 52.1 g of crude oil. The oil was crystallized from heptane (225mL) to provide2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoicacid (39.0 g, 73%). ¹H NMR (400 MHz, DMSO-d₆) δ 14.22 (s, 1H), 7.80 (t,J=8.6 Hz, 1H), 7.45-7.33 (m, 1H), 7.19 (dd, J=9.3, 2.2 Hz, 1H), 6.87 (d,J=8.9 Hz, 1H), 3.87 (s, 3H) ppm.

Step 2: methyl6-[[2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyrimidine-4-carboxylate

To a solution of2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoicacid (350 mg, 0.802 mmol) and DMF (10 μL, 0.13 mmol) in dichloromethane(9 mL) at 0° C. was added oxalyl chloride (250 μL, 2.87 mmol) dropwiseunder nitrogen. The ice bath was removed after 1 hour and the mixturewas stirred at room temperature for 1 hour. The solution wasconcentrated in vacuo to afford2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoylchloride. A portion of the acid chloride (50 mg, 0.11 mmol) wasdissolved in NMP (0.3 mL) and added to a mixture of methyl6-aminopyrimidine-4-carboxylate (25.5 mg, 0.166 mmol) and DIEA (57 mg,77 μL, 0.44 mmol) in NMP (0.3 mL). The mixture was stirred at roomtemperature for 16 hours. Purification by reverse phase HPLC (30-99%acetonitrile/5 mM HCl) provided methyl6-[[2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyrimidine-4-carboxylate(10 mg, 16%). ESI-MS m z calc. 567.07, found 568.0 (M+1)⁺; LC/MSretention time (Method B): 2.0 minutes.

Step 3:6-[[2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyrimidine-4-carboxamide(329)

Methyl6-[[2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyrimidine-4-carboxylate(10 mg, 0.018 mmol) was dissolved in a solution of ammonia in methanol(500 μL of 7 M, 3.5 mmol) and stirred at room temperature for 16 hours.The mixture was filtered, concentrated and purified by reverse phaseHPLC (40-70% acetonitrile/5 mM HCl) to provide6-[[2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyrimidine-4-carboxamide(6.8 mg, 70%). ESI-MS m z calc. 552.07, found 553.0 (M+1)⁺; LC/MSretention time (Method B): 1.85 minutes. ¹H NMR (400 MHz, DMSO-d₆) δ12.10 (s, 1H), 9.04 (s, 1H), 8.68 (s, 1H), 8.29 (s, 1H), 7.96 (t, 1H),7.84 (t, J=8.6 Hz, 1H), 7.40 (t, J=8.6 Hz, 1H), 7.22 (dd, J=9.3, 2.1 Hz,1H), 6.90 (d, J=8.9 Hz, 1H), 3.86 (d, J=1.1 Hz, 3H) ppm.

The compounds set forth in Table 34 were prepared by methods analogousto the preparation of compound 329, Example 134 above), i.e., amidecoupling with2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoicacid was followed by conversion of the ester to the correspondingcarboxamide via treatment with methanolic ammonia.

TABLE 34 Additional Compounds Prepared by Methods Analogous to Example134 Cmpd No. Compound Name LC/MS NMR (shifts in ppm) 3302-[[2-fluoro-6-[3-fluoro-2- ESI-MS m/z ¹H NMR (400 MHz, DMSO-d₆) δmethoxy-4- calc. 551.07, 11.57 (s, 1H), 8.54 (s, 1H), 8.48 (d,(trifluoromethoxy)phenoxy]-3- found 552.0 J = 5.1 Hz, 1H), 8.26 (s, 1H),7.81 (t, (trifluoromethyl)benzoyl]ami- (M + 1)⁺; LC/MS J = 8.6 Hz, 1H),7.72 (s, 1H), 7.56 (d, no]pyridine-4-carboxamide retention time J = 5.2Hz, 1H), 7.40 (t, J = 8.6 Hz, (Method C): 1H), 7.21 (dd, J = 9.3, 2.1Hz, 1H), 2.44 minutes 6.87 (d, J = 8.9 Hz, 1H), 3.86 (d, J = 3.1 Hz,3H). 331 5-[[2-fluoro-6-[3-fluoro-2- ESI-MS m/z ¹H NMR (400 MHz,DMSO-d₆) δ methoxy-4- calc. 552.07, 11.70 (s, 1H), 9.20 (s, 2H), 8.17(s, (trifluoromethoxy)phenoxy]-3- found 553.0 1H), 7.89 (t, J = 8.6 Hz,1H), 7.78 (s, (trifluoromethyl)benzoyl]ami- (M + 1)⁺; LC/MS 1H), 7.42(t, J = 8.6 Hz, 1H), 7.25 no]pyrimidine-2-carboxamide retention time(dd, J = 9.5, 2.1 Hz, 1H), 6.95 (d, J = (Method C): 8.9 Hz, 1H), 3.87(d, J = 1.2 Hz, 3H). 2.35 minutes

Example 135N-(2-carbamoyl-4-pyridyl)-3-fluoro-5-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine-4-carboxamide(332)

Step 1: ethyl3-fluoro-5-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine-4-carboxylate

Ethyl 3,5-difluoro-2-(trifluoromethyl)pyridine-4-carboxylate (5.0 g, 20mmol, see US 2019/0016671, Example 12, Step 1, which is incorporated byreference) was dissolved in anhydrous DMF (30 mL) under a nitrogenatmosphere and then cooled to 3° C.3-Fluoro-2-methoxy-4-(trifluoromethoxy)phenol (4.52 g, 20.0 mmol, seeExample 113, Step 1) was added in one portion followed by Cs₂CO₃ (12.84g, 39.41 mmol). An exotherm increasing the mixture temperature to 9° C.was observed. The mixture was stirred in an ice bath for 1 hour, thenallowed to warm to room temperature and stirred for 1.5 hours. Themixture was partitioned between ethyl acetate (150 mL) and water (150mL) and the layers separated. The organic layer was washed with water(150 mL) and brine (50 mL), dried over Na₂SO₄, filtered and concentratedin vacuo. Purification by silica gel chromatography (0-10% ethylacetate/heptane) provided ethyl3-fluoro-5-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine-4-carboxylate(8310 mg, 92%). ESI-MS m z calc. 461.05, no ionization observed; LC/MSretention time (Method F): 1.12 minutes. ¹H NMR (400 MHz, CDCl₃) δ 7.97(s, 1H), 7.08 (ddt, J=8.8, 7.6, 1.2 Hz, 1H), 6.98 (dd, J=9.2, 2.2 Hz,1H), 4.45 (q, J=7.1 Hz, 2H), 3.93 (d, J=1.9 Hz, 3H), 1.39 (t, J=7.1 Hz,3H) ppm.

Step 2:3-fluoro-5-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine-4-carboxylicacid

To a solution of ethyl3-fluoro-5-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine-4-carboxylate(2.0 g, 4.3 mmol) in THF (6 mL) was added LiOH hydrate (550 mg, 13.1mmol) and water (2 mL). The resulting mixture was stirred at roomtemperature for 24 hours. The volatiles were removed in vacuo and theremaining aqueous mixture was acidified with 1 M aqueous HCl. Theresulting solid was collected by filtration, washed with water and driedin vacuo. The solid was dissolved in ethyl acetate, dried over Na₂SO₄,filtered and concentrated in vacuo to provide3-fluoro-5-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine-4-carboxylicacid (1.76 g, 94%) as white solid. ESI-MS m z calc. 433.02, found 434.0(M+1)⁺; LC/MS retention time (Method B): 1.78 minutes. ¹H NMR (400 MHz,DMSO-d₆) δ 8.35 (s, 1H), 7.37 (ddd, J=9.3, 8.0, 1.2 Hz, 1H), 7.21 (dd,J=9.3, 2.2 Hz, 1H), 3.89 (d, J=1.3 Hz, 3H) ppm.

Step 3:N-(2-carbamoyl-4-pyridyl)-3-fluoro-5-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine-4-carboxamide(332)

A solution of3-fluoro-5-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine-4-carboxylicacid (40 mg, 0.092 mmol) and DMF (2 μL, 0.03 mmol) in dichloromethane(0.5 mL) at 0° C. was treated with oxalyl chloride (48 μL, 0.55 mmol).The mixture was stirred for 30 minutes at room temperature. The mixturewas concentrated in vacuo, and the resulting acid chloride was dissolvedin NMP (0.5 mL) and slowly added to a mixture of4-aminopyridine-2-carboxamide (38 mg, 0.28 mmol) and DIEA (72 mg, 97 μL,0.55 mmol) in NMP (0.4 mL). The mixture was allowed to warm to roomtemperature and stirred for 16 hours. Purification by reverse phase HPLC(acetonitrile/5 mM HCl gradient) providedN-(2-carbamoyl-4-pyridyl)-3-fluoro-5-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine-4-carboxamide(14 mg, 27%). ESI-MS m z calc. 552.07, found 553.3 (M+1)⁺; LC/MSretention time (Method B): 1.19 minutes. ¹H NMR (400 MHz, DMSO-d₆) δ11.78 (s, 1H), 8.59 (d, J=5.5 Hz, 1H), 8.46 (s, 1H), 8.30 (s, 1H), 8.17(s, 1H), 7.82-7.77 (m, 1H), 7.73 (s, 1H), 7.38 (t, J=8.5 Hz, 1H), 7.31(d, J=9.5 Hz, 1H), 3.88 (d, J=1.4 Hz, 3H) ppm.

Example 136N-(2-carbamoyl-4-pyridyl)-5-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-3-methoxy-2-(trifluoromethyl)pyridine-4-carboxamide(333)

Step 1:5-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-3-methoxy-2-(trifluoromethyl)pyridine-4-carboxylicacid

A solution of ethyl3-fluoro-5-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine-4-carboxylate(600 mg, 1.30 mmol, see Example 135, Step 1) in a solution of sodiummethoxide (10 mL of 25% w/w in methanol, 44 mmol) was stirred at roomtemperature for 70 minutes. The mixture was concentrated and acidifiedwith 1 M aqueous HCl. The aqueous mixture was extracted with ethylacetate (3×), and the combined extracts were washed with brine, driedover Na₂SO₄, filtered and concentrated in vacuo. The residue waspurified by reverse phase HPLC (30-99% acetonitrile/5 mM HCl) to provide5-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-3-methoxy-2-(trifluoromethyl)pyridine-4-carboxylicacid (166 mg, 29%) as white solid. ESI-MS m z calc. 445.04, found 446.0(M+1)⁺; LC/MS retention time (Method B): 1.79 minutes. ¹H NMR (400 MHz,DMSO-d₆) δ 14.61 (s, 1H), 8.17 (s, 1H), 7.36 (t, J=8.7 Hz, 1H), 7.15(dd, J=9.3, 2.1 Hz, 1H), 3.98 (s, 3H), 3.89 (d, J=1.2 Hz, 3H) ppm.

Step 2:N-(2-carbamoyl-4-pyridyl)-5-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-3-methoxy-2-(trifluoromethyl)pyridine-4-carboxamide

A solution of5-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-3-methoxy-2-(trifluoromethyl)pyridine-4-carboxylicacid (30 mg, 0.067 mmol) and DMF (one drop) in dichloromethane (375 μL)at 0° C. was slowly treated with oxalyl chloride (12 μL, 0.14 mmol). Theresulting mixture was stirred at 0° C. for 5 minutes and then for 20minutes at room temperature. The mixture was concentrated in vacuo. Theresulting acid chloride dissolved in NMP (375 μL) and added slowly to asolution of 4-aminopyridine-2-carboxamide (27.7 mg, 0.202 mmol) and DIEA(70 μL, 0.40 mmol) in NMP (300 μL) at 0° C. The mixture was allowed towarm to room temperature and stirred for 16 hours. Purification byreverse phase HPLC (acetonitrile/5 mM HCl gradient) providedN-(2-carbamoyl-4-pyridyl)-5-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-3-methoxy-2-(trifluoromethyl)pyridine-4-carboxamide(24.8 mg, 64%). ESI-MS m z calc. 564.09, found 565.1 (M+1)⁺; LC/MSretention time (Method B): 1.76 minutes. ¹H NMR (400 MHz, DMSO-d₆) δ11.56 (s, 1H), 8.57 (d, J=5.5 Hz, 1H), 8.32 (d, J=2.2 Hz, 1H), 8.23 (s,1H), 8.12 (d, J=2.7 Hz, 1H), 7.79 (dd, J=5.5, 2.2 Hz, 1H), 7.68 (d,J=2.7 Hz, 1H), 7.36 (t, J=8.7 Hz, 1H), 7.21 (dd, J=9.3, 2.1 Hz, 1H),3.97 (s, 3H), 3.86 (d, J=1.2 Hz, 3H) ppm.

Example 137N-(2-carbamoyl-5-methyl-4-pyridyl)-5-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-3-methoxy-2-(trifluoromethyl)pyridine-4-carboxamide(334)

Step 1: methyl4-[[3-fluoro-5-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine-4-carbonyl]amino]-5-methyl-pyridine-2-carboxylate

A solution of3-fluoro-5-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine-4-carboxylicacid (40 mg, 0.09 mmol, see Example 135, Step 2) and DMF (2 μL, 0.03mmol) in dichloromethane (0.5 mL) at 0° C. was treated with oxalylchloride (70 mg, 48 μL, 0.55 mmol). The resulting mixture was stirredfor 30 minutes at room temperature, and then concentrated in vacuo. Theresidue was dissolved in NMP (0.5 mL) and added slowly to a solution ofmethyl 4-amino-5-methyl-pyridine-2-carboxylate (46 mg, 0.28 mmol,Preparation 1) and DIEA (97 μL, 0.55 mmol) in NMP (0.4 mL) at 0° C. Themixture was allowed to warm to room temperature and stirred for 16hours. Purification by HPLC (acetonitrile/5 mM HCl gradient) providedmethyl4-[[3-fluoro-5-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine-4-carbonyl]amino]-5-methyl-pyridine-2-carboxylate(26.8 mg, 49%). ESI-MS m z calc. 581.08, found 582.1 (M+1)⁺; LC/MSretention time (Method B): 1.26 minutes. ¹H NMR (400 MHz, DMSO-d₆) δ10.79 (s, 1H), 8.59 (s, 1H), 8.47 (d, J=13.3 Hz, 2H), 7.39 (t, J=8.7 Hz,1H), 7.26 (dd, J=9.4, 2.0 Hz, 1H), 3.93-3.85 (m, 6H), 2.32 (s, 3H) ppm.

Step 2:N-(2-carbamoyl-5-methyl-4-pyridyl)-5-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-3-methoxy-2-(trifluoromethyl)pyridine-4-carboxamide(334)

Methyl4-[[3-fluoro-5-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine-4-carbonyl]amino]-5-methyl-pyridine-2-carboxylate(21 mg, 0.035 mmol) was dissolved in ammonia in methanol (1.5 mL of 7 M,11 mmol) and stirred at room temperature for 16 hours. The mixture wasconcentrated in vacuo and purified by reverse phase HPLC (acetonitrile/5mM HCl gradient) to provideN-(2-carbamoyl-5-methyl-4-pyridyl)-5-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-3-methoxy-2-(trifluoromethyl)pyridine-4-carboxamide(14 mg, 68%) as a white solid. ESI-MS m z calc. 578.10, found 579.1(M+1)⁺; LC/MS retention time (Method C): 2.43 minutes. ¹H NMR (400 MHz,DMSO-d₆) δ 10.70 (s, 1H), 8.48 (d, J=2.9 Hz, 2H), 8.21 (s, 1H), 8.07 (s,1H), 7.63 (s, 1H), 7.38 (t, J=8.7 Hz, 1H), 7.20 (dd, J=9.3, 2.1 Hz, 1H),4.03 (s, 3H), 3.89 (d, J=1.2 Hz, 3H), 2.30 (s, 3H) ppm.

Example 1385-[[5-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-3-methyl-2-(trifluoromethyl)pyridine-4-carbonyl]amino]pyrimidine-2-carboxamide(335)

Step 1:5-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-3-methyl-2-(trifluoromethyl)pyridine-4-carboxylicacid

To a solution of3-fluoro-5-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine-4-carboxylicacid (900 mg, 2.08 mmol, see Example 135, Step 2) in THF (5 mL) wasslowly added a solution of methyl magnesium bromide (9.0 mL of 1 M indiethyl ether, 9 mmol) under nitrogen atmosphere at 0° C. (exothermobserved). The mixture was removed from the ice bath and heated at 55°C. for 2 hours. The mixture was diluted with 1 M aqueous HCl andextracted with ethyl acetate (3×). The combined organic extracts wereconcentrated in vacuo and purified by reverse phase HPLC (10-99%acetonitrile/5 mM HCl) to provide5-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-3-methyl-2-(trifluoromethyl)pyridine-4-carboxylicacid (621 mg, 70%). ESI-MS m z calc. 429.05, found 430.4 (M+1)⁺; LC/MSretention time (Method A): 0.68 minutes. ¹H NMR (400 MHz, DMSO-d₆) δ14.46 (br s, 1H), 8.27 (s, 1H), 7.35 (ddd, J=9.4, 8.1, 1.3 Hz, 1H), 7.12(dd, J=9.3, 2.2 Hz, 1H), 3.88 (d, J=1.1 Hz, 3H), 2.45 (d, J=2.0 Hz, 3H)ppm.

Step 2: methyl5-[[5-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-3-methyl-2-(trifluoromethyl)pyridine-4-carbonyl]amino]pyrimidine-2-carboxylate

A mixture of5-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-3-methyl-2-(trifluoromethyl)pyridine-4-carboxylicacid (30 mg, 0.070 mmol) and DMF (1 drop) in dichloromethane (0.5 mL) at0° C. was treated with oxalyl chloride (37 μL, 0.42 mmol). The resultingmixture was stirred at room temperature for 30 minutes. The mixture wasconcentrated in vacuo. The resulting acid chloride dissolved in NMP (0.4mL) and added to a mixture of methyl 5-aminopyrimidine-2-carboxylate (32mg, 0.21 mmol) and DIEA (73 μL, 0.42 mmol) in NMP (0.3 mL) at 0° C. Themixture was stirred overnight, concentrated in vacuo, and purified byreverse phase HPLC (1-99% acetonitrile/5 mM HCl gradient) to providemethyl5-[[5-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-3-methyl-2-(trifluoromethyl)pyridine-4-carbonyl]amino]pyrimidine-2-carboxylate(38.8 mg, 98%). ESI-MS m z calc. 564.09, found 565.1 (M+1)⁺; LC/MSretention time (Method A): 0.47 minutes.

Step 3:5-[[5-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-3-methyl-2-(trifluoromethyl)pyridine-4-carbonyl]amino]pyrimidine-2-carboxamide(335)

Methyl5-[[5-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-3-methyl-2-(trifluoromethyl)pyridine-4-carbonyl]amino]pyrimidine-2-carboxylate(15 mg, 0.027 mmol) was dissolved a solution of ammonia in methanol (1mL of 7 M, 7 mmol) and stirred at room temperature for 16 hours. Themixture was concentrated in vacuo and purified by reverse phase HPLC(10-99% acetonitrile/5 mM HCl) to provide5-[[5-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-3-methyl-2-(trifluoromethyl)pyridine-4-carbonyl]amino]pyrimidine-2-carboxamide(13.9 mg, 95%). ESI-MS m z calc. 549.09, found 550.1 (M+1)⁺; LC/MSretention time (Method C): 2.25 minutes. ¹H NMR (400 MHz, DMSO-d₆) δ11.57 (s, 1H), 9.16 (s, 2H), 8.34 (s, 1H), 8.13 (s, 1H), 7.74 (s, 1H),7.34 (d, J=8.5 Hz, 1H), 7.18 (d, J=9.8 Hz, 1H), 3.86 (d, J=1.2 Hz, 3H),3.29 (s, 3H) ppm.

Example 139N-(2-carbamoyl-5-methyl-4-pyridyl)-5-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-3-methyl-2-(trifluoromethyl)pyridine-4-carboxamide(336)

This compound was made in an analogous fashion to the synthesis ofcompound 335 in Example 138, except employing methyl4-amino-5-methyl-pyridine-2-carboxylate (Preparation 1) in the amideformation step, followed by conversion of the ester to the correspondingcarboxamide via treatment with methanolic ammonia. The yieldofN-(2-carbamoyl-5-methyl-4-pyridyl)-5-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-3-methyl-2-(trifluoromethyl)pyridine-4-carboxamideafter purification was 5.393 g (95%). ESI-MS m z calc. 562.11, found563.1 (M+1)⁺; 561.2 (M−1)⁻; LC/MS retention time (Method E): 3.21minutes. ¹H NMR (400 MHz, DMSO-d₆) δ 10.62 (s, 1H), 8.54-8.45 (m, 2H),8.31 (s, 1H), 8.07 (d, J=2.9 Hz, 1H), 7.62 (d, J=2.9 Hz, 1H), 7.38 (tq,J=8.1, 1.2 Hz, 1H), 7.18 (dd, J=9.3, 2.2 Hz, 1H), 3.89 (d, J=1.2 Hz,3H), 2.53 (q, J=1.8 Hz, 3H), 2.29 (s, 3H) ppm.

Example 140N-(6-carbamoyl-3-pyridyl)-5-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-3-methyl-2-(trifluoromethyl)pyridine-4-carboxamide(337)

This compound was made in an analogous fashion to the synthesis ofcompound 335 in Example 138, except employing5-aminopyridine-2-carboxamide in the amide formation step. The yield ofN-(6-carbamoyl-3-pyridyl)-5-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-3-methyl-2-(trifluoromethyl)pyridine-4-carboxamideafter purification was 23.1 mg (45%). ESI-MS m z calc. 548.09, found549.1 (M+1)⁺; LC/MS retention time (Method C): 2.4 minutes. ¹H NMR (400MHz, DMSO-d₆) δ 11.37 (s, 1H), 8.82 (s, 1H), 8.33 (s, 1H), 8.27 (d,J=8.7 Hz, 1H), 8.09-7.99 (m, 2H), 7.58 (s, 1H), 7.35 (t, J=8.6 Hz, 1H),7.17 (d, J=9.5 Hz, 1H), 3.86 (d, J=1.2 Hz, 3H), 2.48 (s, 3H) ppm.

Example 1414-[[6-[2-ethoxy-4-(trifluoromethoxy)phenoxy]-2-fluoro-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(346)

Step 1:6-[2-ethoxy-4-(trifluoromethoxy)phenoxy]-2-fluoro-3-(trifluoromethyl)benzoicacid

A solution of 2-ethoxy-4-(trifluoromethoxy)phenol (4.45 g, 20.0 mmol,Preparation 10) in toluene (150 mL) was bubbled with nitrogen for 10minutes. 6-Bromo-2-fluoro-3-(trifluoromethyl)benzoic acid (5.755 g,20.05 mmol), Cs₂CO₃ (13.26 g, 40.70 mmol) and copper (I) iodide (768 mg,4.03 mmol) were added and the mixture heated at 100° C. under nitrogenfor 5 hours. The cooled mixture was washed with saturated aqueous NH₄Clsolution and 0.1 M aqueous HCl. The organic layer was dried over MgSO₄,filtered and concentrated in vacuo to provide6-[2-ethoxy-4-(trifluoromethoxy)phenoxy]-2-fluoro-3-(trifluoromethyl)benzoicacid (8.04 g, 94%). ESI-MS m z calc. 428.05, found 427.6 (M−1)⁻; LC/MSretention time (Method F): 0.64 minutes. The material was taken to thenext step without further purification.

Step 2:4-[[6-[2-ethoxy-4-(trifluoromethoxy)phenoxy]-2-fluoro-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(346)

To a solution of6-[2-ethoxy-4-(trifluoromethoxy)phenoxy]-2-fluoro-3-(trifluoromethyl)benzoicacid (300 mg, 0.701 mmol) and DMF (6 μL, 0.07 mmol) in dichloromethane(10 mL) at 0° C. was added oxalyl chloride (610 μL, 6.99 mmol) dropwise(gas evolution). The mixture was stirred for 1 hour and concentrated invacuo. The resulting acid chloride was dissolved in dichloromethane (10mL) and added dropwise to a stirring solution of methyl4-aminopyridine-2-carboxylate (118 mg, 0.776 mmol), DMAP (86 mg, 0.70mmol) and DIPEA (365 μL, 2.10 mmol) in dichloromethane (10 mL). Themixture was stirred for 72 hours. The mixture was concentrated in vacuo,and the residue stirred overnight in a solution of ammonia in methanol(5 mL of 7 M, 35 mmol). Purification by reverse phase HPLC (47-95%acetonitrile/0.1% ammonium hydroxide) provided4-[[6-[2-ethoxy-4-(trifluoromethoxy)phenoxy]-2-fluoro-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(55.8 mg, 14%). ESI-MS m z calc. 547.10, found 548.1 (M+1)⁺; 546.2(M−1)⁻; LC/MS retention time (Method F): 0.96 minutes. ¹H NMR (400 MHz,CDCl₃) δ 9.18 (s, 1H), 8.60-8.52 (m, 1H), 8.45 (dd, J=5.6, 2.2 Hz, 1H),7.97-7.88 (m, 2H), 7.59 (ddd, J=8.6, 7.8, 0.7 Hz, 1H), 7.30-7.21 (m,1H), 6.94 (pd, J=2.7, 1.4 Hz, 2H), 6.62 (ddd, J=8.9, 1.4, 0.7 Hz, 1H),5.48 (d, J=4.0 Hz, 1H), 4.12 (q, J=7.0 Hz, 2H), 1.29 (t, J=7.0 Hz, 3H)ppm.

Example 1424-[[6-[2-ethoxy-4-(trifluoromethoxy)phenoxy]-2-fluoro-4-methoxy-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(347)

A mixture of4-[[6-bromo-2-fluoro-4-methoxy-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(350 mg, 0.803 mmol, see Example 109, Step 2),2-ethoxy-4-(trifluoromethoxy)phenol (170 mg, 0.765 mmol, Preparation 10)and Cs₂CO₃ (280 mg, 0.859 mmol) in toluene (10 mL) was bubbled withnitrogen for 10 minutes, then copper (I) iodide (53 mg, 0.28 mmol)added. The mixture was heated at 100° C. under nitrogen with vigorousstirring for 1 hour. The cooled mixture was acidified with aqueous HCl,filtered and the aqueous layer was extracted with ethyl acetate (3×50mL). The combined extracts were washed with brine, dried over MgSO₄,filtered and concentrated in vacuo. Purification by silica gelchromatography (0-100% ethyl acetate/heptane), followed by reverse phaseHPLC purification (47-95% acetonitrile/0.1% ammonium hydroxide) provided4-[[6-[2-ethoxy-4-(trifluoromethoxy)phenoxy]-2-fluoro-4-methoxy-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(52.1 mg, 11%) as a white powder. ESI-MS m z calc. 577.11, found 578.5(M+1)⁺; 576.4 (M−1)⁻; LC/MS retention time (Method E): 3.39 minutes. ¹HNMR (500 MHz, DMSO-d₆) δ 11.20 (s, 1H), 8.52 (d, J=5.5 Hz, 1H), 8.26 (d,J=2.1 Hz, 1H), 8.08 (d, J=2.8 Hz, 1H), 7.79 (dd, J=5.6, 2.3 Hz, 1H),7.64 (d, J=2.9 Hz, 1H), 7.31 (d, J=8.8 Hz, 1H), 7.16 (d, J=2.7 Hz, 1H),6.96 (ddd, J=8.9, 2.8, 1.3 Hz, 1H), 6.45 (s, 1H), 4.05 (q, J=6.9 Hz,2H), 3.80 (s, 3H), 1.17 (t, J=6.9 Hz, 3H) ppm.

Example 1434-[[6-(3,4-difluoro-2-methyl-phenoxy)-2-fluoro-4-methoxy-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(348)

Step 1:6-(3,4-difluoro-2-methyl-phenoxy)-2-fluoro-4-methoxy-3-(trifluoromethyl)benzoicacid

A mixture of 6-bromo-2-fluoro-4-methoxy-3-(trifluoromethyl)benzoic acid(900 mg, 2.84 mmol, see US 2019/0016671, Example 129, Step 3, which isincorporated by reference), 3,4-difluoro-2-methyl-phenol (410 mg, 2.85mmol, Preparation 11) and Cs₂CO₃ (1.110 g, 3.407 mmol) in toluene (5 mL)was bubbled with nitrogen for 10 minutes, then copper (I) iodide (210mg, 1.10 mmol) added. The mixture was heated at 100° C. with vigorousstirring for 1 hour. The cooled mixture was acidified with 1 M aqueousHCl, filtered and the aqueous layer was extracted into ethyl acetate(3×50 mL). The organic layer was washed with brine, dried over MgSO₄,filtered and concentrated in vacuo. Purification by silica gelchromatography (0-70% ethyl acetate/hexanes) provided6-(3,4-difluoro-2-methyl-phenoxy)-2-fluoro-4-methoxy-3-(trifluoromethyl)benzoicacid (552 mg, 51%). ESI-MS m z calc. 380.05, found 381.2 (M+1)⁺; LC/MSretention time (Method A): 0.67 minutes. ¹H NMR (400 MHz, DMSO-d₆) δ13.72 (s, 1H), 7.35 (q, J=9.5 Hz, 1H), 6.96 (ddd, J=9.2, 4.1, 1.9 Hz,1H), 6.39 (s, 1H), 3.77 (s, 3H), 2.15 (d, J=2.0 Hz, 3H) ppm.

Step 2: methyl4-[[6-(3,4-difluoro-2-methyl-phenoxy)-2-fluoro-4-methoxy-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxylate

A solution of6-(3,4-difluoro-2-methyl-phenoxy)-2-fluoro-4-methoxy-3-(trifluoromethyl)benzoicacid (200 mg, 0.526 mmol) in dichloromethane (10 mL) was cooled to 0° C.and oxalyl chloride (150 μL, 1.72 mmol) added followed by DMF (3 μL,0.04 mmol). The mixture was stirred for 1 hour and concentrated invacuo. The resulting acid chloride was dissolved in dichloromethane (10mL) and methyl 4-aminopyridine-2-carboxylate (80 mg, 0.53 mmol) and TEA(150 μL, 1.08 mmol) added. The mixture was stirred at room temperatureovernight and concentrated in vacuo. Purification by silica gelchromatography (0-100% ethyl acetate/heptane) provided methyl4-[[6-(3,4-difluoro-2-methyl-phenoxy)-2-fluoro-4-methoxy-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxylate(75 mg, 28%) as a white powder. ESI-MS m z calc. 514.10, found 515.5(M+1)⁺; 513.4 (M−1)⁻; LC/MS retention time (Method F): 0.94 minutes. ¹HNMR (500 MHz, DMSO-d₆) δ 11.34 (s, 1H), 8.62 (d, J=5.5 Hz, 1H), 8.32 (d,J=2.1 Hz, 1H), 7.79 (dd, J=5.4, 2.2 Hz, 1H), 7.36 (q, J=9.4 Hz, 1H),7.07-6.99 (m, 1H), 6.44 (s, 1H), 3.89 (s, 3H), 3.81 (s, 3H), 2.13 (d,J=2.0 Hz, 3H) ppm.

Step 3:4-[[6-(3,4-difluoro-2-methyl-phenoxy)-2-fluoro-4-methoxy-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(348)

Methyl4-[[6-(3,4-difluoro-2-methyl-phenoxy)-2-fluoro-4-methoxy-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxylate(75 mg, 0.15 mmol) was dissolved in a solution of ammonia in methanol (3mL of 7 M, 21 mmol) and the mixture stirred at room temperature for 3hours. The mixture was concentrated in vacuo and purified by reversephase HPLC (38-53% acetonitrile/0.1% ammonium hydroxide) to provide4-[[6-(3,4-difluoro-2-methyl-phenoxy)-2-fluoro-4-methoxy-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(41.8 mg, 57%) as a white powder. ESI-MS m z calc. 499.10, found 500.5(M+1)⁺; 498.4 (M−1)⁻; LC/MS retention time (Method E): 3.16 minutes. ¹HNMR (500 MHz, DMSO-d₆) δ 11.28 (s, 1H), 8.54 (d, J=5.5 Hz, 1H), 8.27 (d,J=2.2 Hz, 1H), 8.09 (d, J=2.9 Hz, 1H), 7.79 (dd, J=5.5, 2.2 Hz, 1H),7.65 (d, J=3.0 Hz, 1H), 7.36 (q, J=9.4 Hz, 1H), 7.04 (ddd, J=9.4, 4.3,1.9 Hz, 1H), 6.43 (s, 1H), 3.81 (s, 3H), 2.13 (d, J=2.0 Hz, 3H) ppm.

Example 1444-benzyl-6-tert-butyl-N-(2-carbamoyl-4-pyridyl)pyridine-3-carboxamide(349)

Step 1: 6-tert-butyl-4-chloro-pyridine-3-carboxylic acid

A solution of ethyl 6-tert-butyl-4-chloro-pyridine-3-carboxylate (2.0 g,8.3 mmol) in methanol (20 mL) was treated with aqueous NaOH (20 mL of2.5 M, 50 mmol) at room temperature and the mixture heated at 70° C. for1 hour. The cooled mixture was diluted with 4 M aqueous HCl (15 mL, 60mmol) and ethyl acetate (50 mL). The layers were separated and theaqueous layer extracted with ethyl acetate (10×30 mL). The combinedorganic extracts were washed with brine (2×20 mL), dried over anhydrousNa₂SO₄, filtered and concentrated in vacuo to provide6-tert-butyl-4-chloro-pyridine-3-carboxylic acid (1.77 g, 100%). ESI-MSm z calc. 213.06, found 214.1 (M+1)⁺; LC/MS retention time (Method A):0.43 minutes.

Step 2: methyl4-[(6-tert-butyl-4-chloro-pyridine-3-carbonyl)amino]pyridine-2-carboxylate

A dichloromethane (15 mL) solution of6-tert-butyl-4-chloro-pyridine-3-carboxylic acid (1.27 g, 5.94 mmol) at0° C. under nitrogen was treated with DMF (20 μL, 0.26 mmol) followed bythe dropwise addition of oxalyl chloride (1.6 mL, 18.3 mmol). Themixture was warmed to room temperature, stirred for 20 minutes and thenconcentrated in vacuo. The residue was dissolved in NMP (12.5 mL),cooled to 0° C. under nitrogen, and treated with methyl4-aminopyridine-2-carboxylate (1.05 g, 6.90 mmol) and DIEA (6 mL, 34mmol). The mixture was warmed to room temperature and stirred for 4hours. The mixture was diluted with saturated aqueous NH₄Cl (20 mL) andextracted with ethyl acetate (30 mL). The organic layer was washed withwater (3×10 mL) and brine (2×10 mL), dried over anhydrous Na₂SO₄,filtered and concentrate in vacuo to provide methyl4-[(6-tert-butyl-4-chloro-pyridine-3-carbonyl)amino]pyridine-2-carboxylate(2.12 g, 103%). ESI-MS m z calc. 347.10, found 348.2 (M+1)⁺; LC/MSretention time (Method B): 1.31 minutes. The compound was used withoutfurther purification.

Step 3:6-tert-butyl-N-(2-carbamoyl-4-pyridyl)-4-chloro-pyridine-3-carboxamide

Methyl4-[(6-tert-butyl-4-chloro-pyridine-3-carbonyl)amino]pyridine-2-carboxylate(1.12 g, 3.22 mmol) was dissolved in a solution of ammonia in methanol(25 mL of 7 M, 175 mmol) at 0° C. and then stirred for 16 hours at roomtemperature. The resulting solid was collected by filtration and washedwith cold methanol (2×5 mL). The solid was collected and dried in vacuoto provide6-tert-butyl-N-(2-carbamoyl-4-pyridyl)-4-chloro-pyridine-3-carboxamide(0.98 g, 91%). ESI-MS m z calc. 332.10, found 333.2 (M+1)⁺; LC/MSretention time (Method B): 1.22 minutes. ¹H NMR (400 MHz, DMSO-d₆) δ11.20 (s, 1H), 8.78 (s, 1H), 8.55 (d, J=5.5 Hz, 1H), 8.36 (d, J=2.1 Hz,1H), 8.10 (d, J=2.8 Hz, 1H), 7.86 (dd, J=5.5, 2.2 Hz, 1H), 7.68 (d,J=14.1 Hz, 2H), 1.35 (s, 9H) ppm.

Step 4:4-benzyl-6-tert-butyl-N-(2-carbamoyl-4-pyridyl)pyridine-3-carboxamide(349)

6-tert-Butyl-N-(2-carbamoyl-4-pyridyl)-4-chloro-pyridine-3-carboxamide(20 mg, 0.06 mmol) and Pd(t-Bu₃P)₂ (11.3 mg, 0.022 mmol) were treatedwith a solution benzyl(bromo)zinc (800 μL of 0.5 M in THF, 0.4 mmol) andthe mixture stirred at room temperature for 20 minutes. The mixture wasfiltered and concentrated in vacuo. The residue was purified by reversephase HPLC (1-99% acetonitrile/5 mM HCl) to provide4-benzyl-6-tert-butyl-N-(2-carbamoyl-4-pyridyl)pyridine-3-carboxamide(7.9 mg, 34%). ESI-MS m z calc. 388.19, found 389.3 (M+1)⁺; LC/MSretention time (Method C): 1.64 minutes. ¹H NMR (400 MHz, DMSO-d₆) δ11.34 (s, 1H), 8.80 (s, 1H), 8.58 (d, J=5.6 Hz, 1H), 8.41 (s, 1H), 8.29(s, 1H), 7.88 (d, J=5.7 Hz, 1H), 7.83 (s, 1H), 7.70 (s, 1H), 7.29-7.12(m, 5H), 4.29 (s, 2H), 1.38 (d, J=1.4 Hz, 9H) ppm.

Example 1456-tert-butyl-N-(2-carbamoyl-4-pyridyl)-4-[(3,4-difluorophenyl)methyl]pyridine-3-carboxamide(350)

This compound was made in an analogous fashion to the synthesis ofcompound 349 in Example 144, except employingbromo-[(3,4-difluorophenyl)methyl]zinc in the final palladium-catalyzedNegishi coupling. The yield of6-tert-butyl-N-(2-carbamoyl-4-pyridyl)-4-[(3,4-difluorophenyl)methyl]pyridine-3-carboxamideafter purification was 3.9 mg (31%). ESI-MS m z calc. 424.17, found425.3 (M+1)⁺; LC/MS retention time (Method C): 1.85 minutes. ¹H NMR (400MHz, DMSO-d₆) δ 11.30 (s, 1H), 8.80 (s, 1H), 8.58 (d, J=5.7 Hz, 1H),8.41 (s, 1H), 8.27 (s, 1H), 7.87 (d, J=5.7 Hz, 1H), 7.81 (s, 1H), 7.68(s, 1H), 7.40-7.23 (m, 2H), 7.13-7.02 (m, 1H), 4.25 (s, 2H), 1.38 (s,9H) ppm.

Example 146N-(2-carbamoyl-4-pyridyl)-4-(4-fluoro-2-methoxy-phenoxy)-2-methyl-6-(trifluoromethyl)pyridine-3-carboxamide(351)

Step 1: ethyl 2-methyl-6-(trifluoromethyl)pyridine-3-carboxylate

2-Methyl-6-(trifluoromethyl)pyridine-3-carboxylic acid (10.0 g, 48.8mmol) was dissolved in acetone (100 mL) and cooled in ice-cool bath.Acetyl chloride (11.0 g, 10.0 mL, 141 mmol) was added dropwise and themixture was heated at 60° C. for 16 hours. The mixture was cooled andsolvent was removed in vacuo, and the residue partitioned betweensaturated aqueous NaHCO₃ and ethyl acetate. The organic layer wasseparated, dried over Na₂SO₄, filtered and concentrated in vacuo toprovide ethyl 2-methyl-6-(trifluoromethyl)pyridine-3-carboxylate (10.5g, 92%). ¹H NMR (400 MHz, CDCl₃) δ 8.32 (d, J=8.0 Hz, 1H), 7.56 (d,J=8.0 Hz, 1H), 4.41 (q, J=7.1 Hz, 2H), 2.87 (s, 3H), 1.41 (t, J=7.2 Hz,3H) ppm.

Step 2: ethyl2-methyl-1-oxido-6-(trifluoromethyl)pyridin-1-ium-3-carboxylate

To a stirring solution of ethyl2-methyl-6-(trifluoromethyl)pyridine-3-carboxylate (8.0 g, 34 mmol) indichloromethane was added urea-hydrogen peroxide (6.8 g, 72 mmol). Themixture was cooled at 0° C. and treated dropwise with trifluoraceticanhydride (15 g, 10 mL, 72 mmol). The mixture was allowed to warm toroom temperature and was treated solid Na₂S₂O₃. The mixture was washedwith 0.5 M aqueous HCl and the layers separated. The organic layer wasdried over Na₂SO₄, filtered and concentrated in vacuo to provide ethyl2-methyl-1-oxido-6-(trifluoromethyl)pyridin-1-ium-3-carboxylate (8.3 g,97%) as white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 7.95 (d, J=8.5 Hz, 1H),7.77 (d, J=8.4 Hz, 1H), 4.38 (q, J=6.9 Hz, 2H), 2.66 (s, 3H), 1.34 (t,J=7.1 Hz, 3H) ppm.

Step 3: ethyl4-chloro-2-methyl-6-(trifluoromethyl)pyridine-3-carboxylate

Ethyl 2-methyl-1-oxido-6-(trifluoromethyl)pyridin-1-ium-3-carboxylate(4.5 g, 18 mmol) and POCl₃ (36 g, 22 mL, 236 mmol) were heated in asealed tube at 120° C. for 5 hours. The cooled mixture was poured ontocrushed ice and Na₂CO₃ added until neutral pH. The mixture waspartitioned between water and ethyl acetate. The organic phase was driedover Na₂SO₄, filtered and concentrated in vacuo. Silica gelchromatography (0-10% ethyl acetate/hexanes) provided ethyl4-chloro-2-methyl-6-(trifluoromethyl)pyridine-3-carboxylate (1.6 g,33%). ¹H NMR (400 MHz, CDCl₃) δ 7.57 (s, 1H), 4.47 (q, J=7.1 Hz, 2H),2.62 (s, 3H), 1.41 (t, J=7.2 Hz, 3H) ppm.

Step 4:4-(4-fluoro-2-methoxy-phenoxy)-2-methyl-6-(trifluoromethyl)pyridine-3-carboxylicacid

A solution of 4-fluoro-2-methoxy-phenol (470 μL, 4.12 mmol) inacetonitrile (10 mL) was treated with Cs₂CO₃ (1.416 g, 4.346 mmol) andethyl 4-chloro-2-methyl-6-(trifluoromethyl)pyridine-3-carboxylate (1.0g, 3.7 mmol). The mixture was stirred at room temperature for 2 hours,and then at 50° C. for 4.5 hours. The mixture was diluted with ethylacetate and washed with 2 M aqueous NaOH. The organic layer dried overMgSO₄, filtered and concentrated. The residue was purified by silica gelchromatography (0-10% ethyl acetate/heptane) to provided ethyl4-(4-fluoro-2-methoxy-phenoxy)-2-methyl-6-(trifluoromethyl)pyridine-3-carboxylate,which was dissolved in dissolved in ethanol (10 mL) and 2 M aqueous NaOH(6 mL, 12 mmol). The mixture was stirred 16 hours, and then additional 2M aqueous NaOH added (2 mL, 4 mmol) and the mixture stirred for 3 hours.The mixture was acidified with 2 M aqueous HCl (9 mL) and extracted intoethyl acetate. The organic layer was separated, dried over MgSO₄,filtered and concentrated to provide4-(4-fluoro-2-methoxy-phenoxy)-2-methyl-6-(trifluoromethyl)pyridine-3-carboxylicacid (919.6 mg, 71%). ESI-MS m z calc. 345.06, found 346.2 (M+1)⁺; LC/MSretention time (Method E): 0.48 minutes.

Step 5:N-(2-carbamoyl-4-pyridyl)-4-(4-fluoro-2-methoxy-phenoxy)-2-methyl-6-(trifluoromethyl)pyridine-3-carboxamide(351)

A solution of4-(4-fluoro-2-methoxy-phenoxy)-2-methyl-6-(trifluoromethyl)pyridine-3-carboxylicacid (77 mg, 0.22 mmol) and DMF (1 drop) in dichloromethane (2 mL) wastreated with oxalyl chloride (75 μL, 0.86 mmol). The mixture was stirredat room temperature for 3.5 hours, and then concentrated. The resultingacid chloride was dissolved in dichloromethane (2 mL) and treated withmethyl 4-aminopyridine-2-carboxylate (36.3 mg, 0.239 mmol) and TEA (60μL, 0.43 mmol). The mixture was stirred at room temperature for 3 hours,and then concentrated and treated with a solution of ammonia in methanol(5 mL of 7 M, 35 mmol). The mixture was stirred for 2 hours, and thenconcentrated and purified by reverse phase HPLC (38-53%acetonitrile/0.1% ammonium hydroxide) to provideN-(2-carbamoyl-4-pyridyl)-4-(4-fluoro-2-methoxy-phenoxy)-2-methyl-6-(trifluoromethyl)pyridine-3-carboxamide(11.6 mg, 11%). ESI-MS m z calc. 464.11, found 465.0 (M+1)⁺; LC/MSretention time (Method E): 2.81 minutes. ¹H NMR (400 MHz, DMSO-d₆) δ11.33 (s, 1H), 8.57 (dd, J=5.5, 0.6 Hz, 1H), 8.35 (dd, J=2.1, 0.6 Hz,1H), 8.10 (s, 1H), 7.87 (dd, J=5.5, 2.2 Hz, 1H), 7.66 (d, J=2.9 Hz, 1H),7.33 (dd, J=8.9, 5.8 Hz, 1H), 7.20 (dd, J=10.7, 2.9 Hz, 1H), 6.89 (ddd,J=8.8, 8.1, 2.9 Hz, 1H), 6.80 (s, 1H), 3.78 (s, 3H), 2.58 (s, 3H) ppm.

Example 1474-[[2-fluoro-4-methoxy-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(352)

Step 1:2-fluoro-4-methoxy-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoicacid

A mixture of 6-bromo-2-fluoro-4-methoxy-3-(trifluoromethyl)benzoic acid(3.0 g, 8.5 mmol, see US 2019/0016671, Example 129, Step 3, which isincorporated by reference), 2-methoxy-4-(trifluoromethoxy)phenol (1.6 g,7.7 mmol) and Cs₂CO₃ (3.0 g, 9.2 mmol) in toluene (30 mL) was bubbledwith nitrogen for 10 minutes, then copper (I) iodide (570 mg, 2.99 mmol)was added. The mixture was heated at 100° C. under nitrogen withvigorous stirring for 30 minutes. The cooled mixture was acidified withaqueous HCl, filtered and the mixture extracted with ethyl acetate (3×50mL). The combined organic extracts were washed with brine, dried overMgSO₄, filtered and concentrated. Purification by silica gelchromatography (0-100% ethyl acetate/hexanes) provided2-fluoro-4-methoxy-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoicacid (3.31 g, 88%) as a pale yellow powder. ESI-MS m/z calc. 444.04,found 445.5 (M+1)⁺; 443.6 (M−1)⁻; LC/MS retention time (Method F): 0.61minutes. ¹H NMR (500 MHz, DMSO-d₆) δ 13.63 (s, 1H), 7.28-7.19 (m, 2H),7.01 (ddd, J=8.8, 2.7, 1.3 Hz, 1H), 6.28 (s, 1H), 3.83 (s, 3H), 3.74 (s,3H) ppm.

Step 2: methyl4-[[2-fluoro-4-methoxy-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxylate

A solution of2-fluoro-4-methoxy-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoicacid (200 mg, 0.450 mmol) in dichloromethane (10 mL) was cooled to 0° C.and treated with oxalyl chloride (100 μL, 1.15 mmol) followed by DMF (2μL, 0.03 mmol). The resulting mixture was stirred for 1 hour and thenconcentrated in vacuo. The residue was dissolved in dichloromethane (10mL) and methyl 4-aminopyridine-2-carboxylate (68.5 mg, 0.450 mmol) andTEA (150 μL, 1.08 mmol) added. The mixture was stirred at roomtemperature overnight then concentrated in vacuo. The residue waspurified by silica gel chromatography (0-100% ethyl acetate/heptane) toprovide methyl4-[[2-fluoro-4-methoxy-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxylate(140 mg, 54%). ESI-MS m z calc. 578.09, found 579.5 (M+1)⁺; 577.6(M−1)⁻; LC/MS retention time (Method F): 0.97 minutes. ¹H NMR (500 MHz,DMSO-d₆) δ 11.28 (s, 1H), 8.61 (d, J=5.5 Hz, 1H), 8.33 (d, J=2.0 Hz,1H), 7.79 (dd, J=5.5, 2.2 Hz, 1H), 7.31 (d, J=8.8 Hz, 1H), 7.19 (d,J=2.8 Hz, 1H), 6.99 (ddd, J=8.8, 2.8, 1.2 Hz, 1H), 6.39 (s, 1H), 3.89(s, 3H), 3.79 (s, 3H), 3.78 (s, 3H) ppm.

Step 3:4-[[2-fluoro-4-methoxy-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(352)

Methyl4-[[2-fluoro-4-methoxy-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxylate(140 mg, 0.242 mmol) was dissolved in a solution of ammonia in methanol(3 mL of 7 M, 21 mmol) and the resulting mixture stirred at roomtemperature for 3 hours. The mixture was concentrated in vacuo and theresidue purified by silica gel chromatography (0-100% ethylacetate/heptane) to provide4-[[2-fluoro-4-methoxy-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(80.1 mg, 57%). ESI-MS m z calc. 563.09, found 564.5 (M+1)⁺; 562.6(M−1)⁻; LC/MS retention time (Method E): 3.28 minutes. H NMR (500 MHz,DMSO-d₆) δ 11.22 (s, 1H), 8.53 (dd, J=5.4, 0.6 Hz, 1H), 8.27 (d, J=2.1Hz, 1H), 8.08 (d, J=2.8 Hz, 1H), 7.80 (dd, J=5.5, 2.2 Hz, 1H), 7.64 (d,J=3.0 Hz, 1H), 7.32 (d, J=8.8 Hz, 1H), 7.20 (d, J=2.9 Hz, 1H), 7.00(ddt, J=8.8, 2.7, 1.2 Hz, 1H), 6.38 (s, 1H), 3.79 (m, 6H) ppm.

Example 1485-[[2-fluoro-4-methoxy-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(353)

This compound was made in an analogous fashion to Example 147, exceptemploying 5-aminopyridine-2-carboxamide in the amide formation step toprovide the final compound. The yield of5-[[2-fluoro-4-methoxy-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamideafter purification was 105.8 mg (41%). ESI-MS m z calc. 563.09, found564.5 (M+1)⁺; 562.5 (M−1)⁻; LC/MS retention time (Method E): 3.25minutes. ¹H NMR (500 MHz, DMSO-d₆) δ 11.14 (s, 1H), 8.82 (d, J=2.4 Hz,1H), 8.23 (dd, J=8.6, 2.5 Hz, 1H), 8.06-7.98 (m, 2H), 7.55 (d, J=2.8 Hz,1H), 7.32 (d, J=8.8 Hz, 1H), 7.20 (d, J=2.7 Hz, 1H), 7.00 (ddt, J=7.7,2.7, 1.3 Hz, 1H), 6.39 (s, 1H), 3.79 (s, 6H) ppm.

Example 1494-[[2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]-5-methyl-1-oxido-pyridin-1-ium-2-carboxamide(354)

Step 1:N-(2-Bromo-5-methyl-4-pyridyl)-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide

To solution of2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoicacid (300 mg, 0.681 mmol, see US 2019/0016671, Example 2, Step 3, whichis incorporated by reference) in dichloromethane (5 mL) at 0° C. wasadded DMF (6 μL, 0.08 mmol) and oxalyl chloride (200 μL, 2.29 mmol)dropwise. The mixture was allowed to warm to room temperature over 3.5hours, and then concentrated in vacuo. The residue was dissolved indichloromethane (5 mL) and cooled to 0° C. The solution was treated with2-bromo-5-methyl-pyridin-4-amine (165 mg, 0.882 mmol) followed by TEA(500 μL, 3.59 mmol). The resulting mixture was allowed to warm to roomtemperature and stirred for 48 hours. The mixture was diluted with water(10 mL) and extracted with dichloromethane (2×10 mL). The combinedorganics were dried over MgSO₄, filtered and concentrated in vacuo.Silica gel chromatography (0-20% ethyl acetate/petroleum ether) providedN-(2-bromo-5-methyl-4-pyridyl)-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide(217 mg, 55%) as an off-white solid. ESI-MS m z calc. 582.00, found583.1 (M+1)⁺; 581.1 (M−1)⁻; LC/MS retention time (Method F): 1.15minutes. ¹H NMR (500 MHz, CDCl₃) δ 8.61 (s, 1H), 8.15 (s, 2H), 7.60-7.57(m, 1H), 7.23 (d, J=8.7 Hz, 1H), 6.98-6.96 (m, 1H), 6.94 (d, J=2.4 Hz,1H), 6.53 (d, J=9.0 Hz, 1H), 3.82 (s, 3H), 2.17 (s, 3H) ppm. ¹⁹F NMR(471 MHz, CDCl₃) δ −58.01, −60.82 (d, J=13.0 Hz), −112.20 (q, J=14.3,13.3 Hz) ppm.

Step 2: Methyl4-[[2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]-5-methyl-pyridine-2-carboxylate

In a pressure tubeN-(2-bromo-5-methyl-4-pyridyl)-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide(217 mg, 0.372 mmol) was dissolved in methanol (10 mL) and TEA (110 μL,0.789 mmol) and Pd(dppf)Cl₂-dichloromethane (60 mg, 0.074 mmol) wereadded. Carbon monoxide was bubbled through the vigorously stirringmixture for 5 minutes. The reaction vessel was sealed and heated to 75°C. for 16 hours. The mixture was cooled to room temperature, filteredthrough a pad of Celite eluting with methanol and concentrated in vacuo.Silica gel chromatography (0-100% ethyl acetate/petroleum ether)provided methyl4-[[2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]-5-methyl-pyridine-2-carboxylate(178.6 mg, 85%). ESI-MS m z calc. 562.10, found 563.2 (M+1)⁺; 561.2(M−1)⁻; LC/MS retention time (Method F): 1.04 minutes. ¹H NMR (500 MHz,CDCl₃) δ 9.06 (s, 1H), 8.54 (s, 1H), 8.20 (s, 1H), 7.59 (d, J=17.0 Hz,1H), 7.24 (d, J=8.7 Hz, 1H), 6.98-6.96 (m, 1H), 6.94-6.93 (m, 1H), 6.55(d, J=9.4 Hz, 1H), 4.03 (s, 3H), 3.83 (s, 3H), 2.30 (s, 3H) ppm. ¹⁹F NMR(471 MHz, CDCl₃) δ −58.01, −60.82 (d, J=12.9 Hz), −112.16-−112.24 (m)ppm.

Step 3:4-[[2-Fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]-5-methyl-pyridine-2-carboxamide

A mixture of methyl4-[[2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]-5-methyl-pyridine-2-carboxylate(178 mg, 0.317 mmol) and ammonia (5 mL of 7 M in methanol, 35 mmol) wasstirred at room temperature for 16 hours. SPM32 silica metal scavenger(150 mg) was added and the mixture was stirred for 15 minutes. Themixture was filtered and the filtrate was concentrated in vacuo. Silicagel chromatography (0-100% ethyl acetate/petroleum ether) provided4-[[2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]-5-methyl-pyridine-2-carboxamide(54.5 mg, 31%) as a white solid. ESI-MS m/z calc. 547.10, found 548.1(M+1)⁺; 546.0 (M−1)⁻; LC/MS retention time (Method E): 3.32 minutes. ¹HNMR (500 MHz, DMSO-d₆) δ 10.58 (s, 1H), 8.49-8.48 (m, 2H), 8.06 (d,J=2.9 Hz, 1H), 7.81 (t, J=8.6 Hz, 1H), 7.61-7.60 (m, 1H), 7.39 (d, J=8.8Hz, 1H), 7.29 (d, J=2.7 Hz, 1H), 7.09-7.06 (m, 1H), 6.66 (d, J=8.9 Hz,1H), 3.82 (s, 3H), 2.33 (s, 3H) ppm. 19F NMR (471 MHz, DMSO-d₆) δ−56.85, −59.11 (d, J=12.2 Hz), −117.84 (q, J=12.5 Hz) ppm.

Step 4:4-[[2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]-5-methyl-1-oxido-pyridin-1-ium-2-carboxamide(354)

A solution of4-[[2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]-5-methyl-pyridine-2-carboxamide(11.6 mg, 0.0209 mmol) in dichloromethane (2.5 mL) at 0° C. was treatedwith meta-chloroperoxybenzoic acid (20 mg, 0.089 mmol). The mixture wasallowed to warm to room temperature and stirred for 3 days. The mixturewas partitioned between dichloromethane and water and the layersseparated (phase separation cartridge). The organic filtrate wasconcentrated in vacuo and purified by reverse phase HPLC (38-53%acetonitrile/0.1% ammonium hydroxide) to provide4-[[2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]-5-methyl-1-oxido-pyridin-1-ium-2-carboxamide(1.7 mg, 14H). ESI-MS m/z calc. 563.09, found 564.4 (M+1)⁺; 562.5 (M−1);LC/MS retention time (Method E): 3.1 minutes. ¹H NMR (500 MHz, CDCl₃) δ10.75 (s, 1H), 9.05 (s, 1H), 8.20 (s, 1H), 8.15 (s, 1H), 7.56 (t, J=8.3Hz, 1H), 7.24 (d, J=8.7 Hz, 1H), 6.96 (dt, J=8.7, 1.8 Hz, 1H), 6.92 (d,J=2.3 Hz, 1H), 6.53 (d, J=8.9 Hz, 1H), 6.01 (s, 1H), 3.82 (s, 3H), 2.27(d, J=0.8 Hz, 3H) ppm.

The compounds set forth in Table 35 were prepared by methods analogousto the preparation of compound4-[[2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]-5-methyl-pyridine-2-carboxamide(see Example 149, Step 3). The amide coupling with the appropriate aminewas followed by conversion of the ester to the corresponding carboxamidevia treatment with methanolic ammonia.

TABLE 35 Additional Compounds Prepared by Methods Analogous to Example149 Cmpd No. Compound Name LC/MS NMR (shifts in ppm) 3556-[[2-fluoro-6-[2-methoxy-4- ESI-MS m/z ¹H NMR (400 MHz, DMSO-d₆) δ(trifluoromethoxy)phenoxy]-3- calc. 534.08, 12.01 (s, 1H), 9.04 (s, 1H),8.69 (s, (trifluoromethyl)benzoyl]ami- found 534.0 1H), 8.29 (s, 1H),7.96 (s, 1H), 7.80 no]pyrimidine-4-carboxamide (M + 1)⁺; LC/MS (m, 1H),7.36 (d, J = 8.6 Hz, 1H), retention time 7.25 (s, 1H), 7.04 (d, J = 8.0Hz, 1H), (Method C): 6.66 (d, J = 8.8 Hz, 1H), 3.78 (s, 3H) 2.47 minutes356 5-[[2-fluoro-6-[2-methoxy-4- ESI-MS m/z(trifluoromethoxy)phenoxy]-3- calc. 534.08,(trifluoromethyl)benzoyl]ami- found 535.0 no]pyridazine-3-carboxamide(M + 1)⁺; LC/MS retention time (Method E): 2.37 minutes 3575-[[2-fluoro-6-[2-methoxy-4- ESI-MS m/z ¹H NMR (400 MHz, DMSO-d₆) δ(trifluoromethoxy)phenoxy]-3- calc. 534.08, 11.60 (s, 1H), 9.20 (s, 2H),8.14 (s, (trifluoromethyl)benzoyl]ami- found 535.0 1H), 7.83 (t, J = 8.6Hz, 1H), 7.74 (s, no]pyrimidine-2-carboxamide (M + 1)⁺; LC/MS 1H), 7.38(d, J = 8.8 Hz, 1H), 7.26 (d, retention time: J = 2.7 Hz, 1H), 7.05(ddd, J = 8.8, 2.3 minutes 2.7, 1.3 Hz, 1H), 6.70 (d, J = 8.9 Hz, (5min. run) 1H), 3.79 (s, 3H).

Example 150N-(6-carbamoyl-3-pyridyl)-5-(3,4-difluoro-2-methoxy-phenoxy)-3-methyl-2-(trifluoromethyl)pyridine-4-carboxamide(358)

Step 1:N-(6-carbamoyl-3-pyridyl)-5-fluoro-3-methyl-2-(trifluoromethyl)pyridine-4-carboxamide

A solution of 5-fluoro-3-methyl-2-(trifluoromethyl)pyridine-4-carboxylicacid (150 mg, 0.672 mmol) in 2-MeTHF (2 mL) and DMF at 0° C. was treateddropwise with oxalyl chloride (120 μL, 1.376 mmol) then allowed to warmto room temperature over 1 hour. The mixture was concentrated in vacuo,then diluted with dichloromethane and evaporated. The residue wasdissolved in 2-MeTHF (2 mL) and treated with5-aminopyridine-2-carboxamide (95 mg, 0.69 mmol). NMP (1 mL) was addedto the suspension to fully dissolve the solid. A solution of K₂CO₃ (280mg, 2.03 mmol) in water (2 mL) was then added and the mixture stirredvigorously at room temperature for 18 hours. The layers were separatedand the aqueous layer extracted with dichloromethane (2×). The combinedextracts were washed with water (2×), dried over Na₂SO₄, filtered andconcentrated in vacuo. Purification by silica gel chromatography (0-100%ethyl acetate/heptanes) providedN-(6-carbamoyl-3-pyridyl)-5-fluoro-3-methyl-2-(trifluoromethyl)pyridine-4-carboxamide(240 mg, 65%). ESI-MS m z calc. 342.07, found 343.0 (M+1)⁺; 341.0(M−1)⁻; LC/MS retention time: 0.64 minutes (Method F). ¹H NMR (500 MHz,DMSO-d₆) δ 11.42 (s, 1H), 8.85 (d, J=2.5 Hz, 1H), 8.82 (s, 1H), 8.30(dd, J=8.5, 2.5 Hz, 1H), 8.09 (d, J=8.5 Hz, 1H), 8.04 (s, 1H), 7.58 (s,1H), 2.48 (d, J=1.8 Hz, 3H) ppm. ¹⁹F NMR (471 MHz, DMSO-d₆) δ −62.94,−125.34 ppm.

Step 2:N-(6-carbamoyl-3-pyridyl)-5-(3,4-difluoro-2-methoxy-phenoxy)-3-methyl-2-(trifluoromethyl)pyridine-4-carboxamide(358)

N-(6-carbamoyl-3-pyridyl)-5-fluoro-3-methyl-2-(trifluoromethyl)pyridine-4-carboxamide(240 mg, 0.435 mmol), 3,4-difluoro-2-methoxy-phenol (70 mg, 0.44 mmol)and K₂CO₃ (120 mg, 0.868 mmol) were combined in acetonitrile (2 mL). Thereaction vial was sealed and heated at 50° C. for 16 hours. The mixturewas cooled to room temperature, filtered and purified directly byreverse phase HPLC (38-53% acetonitrile/0.1% ammonium hydroxide) toprovideN-(6-carbamoyl-3-pyridyl)-5-(3,4-difluoro-2-methoxy-phenoxy)-3-methyl-2-(trifluoromethyl)pyridine-4-carboxamide(22.0 mg, 10%) as a white solid. ESI-MS m z calc. 482.10, found 483.0(M+1)⁺; 481.0 (M−1)⁻; LC/MS retention time (Method E): 2.86 minutes. ¹HNMR (500 MHz, DMSO-d₆) δ 11.27 (s, 1H), 8.71 (s, 1H), 8.29-8.19 (m, 1H),8.13 (s, 1H), 7.98 (d, J=8.5 Hz, 1H), 7.94 (s, 1H), 7.45 (s, 1H), 7.21(q, J=9.4 Hz, 1H), 7.13-7.03 (m, 1H), 3.86 (d, J=1.0 Hz, 3H), 2.46 (d,J=1.9 Hz, 3H) ppm. ¹⁹F NMR (471 MHz, DMSO-d6) δ −62.60, −139.00, −152.37ppm.

Example 151N-(6-carbamoyl-3-pyridyl)-5-(2-chloro-4-fluoro-phenoxy)-3-methyl-2-(trifluoromethyl)pyridine-4-carboxamide(359)

This compound was made in an analogous fashion to the synthesis ofcompound 358 in Example 150, except employing 2-chloro-4-fluoro-phenolin the final ether formation step. The yield ofN-(6-carbamoyl-3-pyridyl)-5-(2-chloro-4-fluoro-phenoxy)-3-methyl-2-(trifluoromethyl)pyridine-4-carboxamidewas 17.1 mg (21%). ESI-MS m z calc. 468.06, found 469.1 (M+1)⁺; 467.1(M−1)⁻; LC/MS retention time (Method E): 2.81 minutes. ¹H NMR (400 MHz,DMSO-d₆) δ 11.33 (s, 1H), 8.82 (s, 1H), 8.27 (dd, J=8.6, 2.5 Hz, 1H),8.16 (s, 1H), 8.06 (d, J=8.5 Hz, 1H), 8.01 (s, 1H), 7.65 (dd, J=8.4, 3.0Hz, 1H), 7.56 (s, 1H), 7.44 (dd, J=9.1, 5.1 Hz, 1H), 7.33 (ddd, J=9.1,8.0, 3.0 Hz, 1H), 2.48 (s, 3H) ppm.

Example 1524-[[2,4-difluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(360)

Step 1: 2,4-difluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoicacid

A mixture of 2-bromo-4,6-difluoro-benzoic acid (750 mg, 3.17 mmol),2-methoxy-4-(trifluoromethoxy)phenol (720 mg, 3.46 mmol) and Cs₂CO₃ (1.1g, 3.4 mmol) in toluene (15 mL) was treated with copper (I) iodide (120mg, 0.630 mmol) and heated to 100° C. for 3 hours in a sealed vial. Themixture was allowed to cool overnight then diluted with ethyl acetate (5mL) and 1 M aqueous HCl (˜5 mL). The layers were separated and theaqueous layer extracted with additional ethyl acetate (2×5 mL). Thecombined organic extracts were dried over Na₂SO₄, filtered andconcentrated in vacuo. Purification silica gel chromatography (0-100%ethyl acetate/heptane) provided2,4-difluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoic acid (495mg, 21%). ESI-MS m z calc. 364.04, found 365.0 (M+1)⁺; 363.0 (M−1)⁻;LC/MS retention time (Method F): 0.6 minutes. ¹H NMR (500 MHz, DMSO-d₆)δ 13.30 (s, 1H), 7.24-7.16 (m, 2H), 7.09 (td, J=9.5, 2.4 Hz, 1H), 6.99(ddd, J=8.7, 2.7, 1.3 Hz, 1H), 6.40 (dt, J=10.2, 1.9 Hz, 1H), 3.80 (s,3H) ppm. The isolated product contained some residual starting materialsbut was taken forward with no additional purification.

Step 2: methyl4-[[2,4-difluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxylate

A solution of2,4-difluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoic acid (495mg, 1.36 mmol) in dichloromethane (5 mL) and DMF (5 μL) at 0° C. wastreated with oxalyl chloride (180 μL, 2.06 mmol) dropwise. The mixturewas allowed to warm to room temperature over 2 hours, concentrated invacuo, then diluted and evaporated twice with dichloromethane. Theresidue was dissolved in dichloromethane (5 mL) and cooled to 0° C.Methyl 4-aminopyridine-2-carboxylate (200 mg, 1.31 mmol) was added inone portion and then TEA (400 μL, 2.87 mmol) added dropwise. The mixturewas allowed to warm to room temperature and stirred overnight. Themixture was diluted with water (3 mL) and the layers separated. Theaqueous layer was extracted with additional dichloromethane (2×3 mL) andthe combined organics dried over Na₂SO₄, filtered and concentrated invacuo. Purification by silica gel chromatography (10-70% ethylacetate/heptane) provided methyl4-[[2,4-difluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxylate(165 mg, 24%) as an off-white solid. ESI-MS m z calc. 498.09, found499.0 (M+1)⁺; 497.0 (M−1)⁻; LC/MS retention time (Method F): 0.92minutes. ¹H NMR (500 MHz, DMSO-d₆) δ 11.31 (s, 1H), 8.61 (d, J=5.5 Hz,1H), 8.36 (d, J=2.1 Hz, 1H), 7.82 (dd, J=5.5, 2.2 Hz, 1H), 7.29 (d,J=8.8 Hz, 1H), 7.23-7.15 (m, 2H), 6.99 (ddd, J=8.8, 2.7, 1.3 Hz, 1H),6.54-6.46 (m, 1H), 3.88 (s, 3H), 3.77 (s, 3H) ppm. ¹⁹F NMR (471 MHz,DMSO-d₆) δ −56.89, −104.52-−105.44 (m), −112.16 (d, J=7.9 Hz) ppm.

Step 3:4-[[2,4-difluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(360)

A solution of methyl5-(2,4-difluoro-6-(2-methoxy-4-(trifluoromethoxy)phenoxy)benzamido)picolinate (165 mg, 0.3311 mmol) in methanol (0.5 mL) was treated with asolution of ammonia in methanol (2 mL of 7 M, 14 mmol) and stirredovernight at room temperature. The mixture was concentrated in vacuo andpurified by reverse phase HPLC (47-95% acetonitrile/0.1% ammoniumhydroxide) to provide4-[[2,4-difluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(146.0 mg, 87%) as a white solid. ESI-MS m z calc. 483.09, found 484.0(M+1)⁺; 482.0 (M−1)+; LC/MS retention time (Method E): 3.04 minutes. ¹HNMR (500 MHz, DMSO-d₆) δ 11.25 (s, 1H), 8.53 (d, J=5.5 Hz, 1H), 8.30 (d,J=2.1 Hz, 1H), 8.08 (d, J=2.8 Hz, 1H), 7.83 (dd, J=5.5, 2.2 Hz, 1H),7.63 (d, J=2.9 Hz, 1H), 7.30 (d, J=8.8 Hz, 1H), 7.22-7.15 (m, 2H), 7.00(ddd, J=8.8, 2.7, 1.2 Hz, 1H), 6.48 (dt, J=10.2, 1.8 Hz, 1H), 3.78 (s,3H) ppm. ¹⁹F NMR (471 MHz, DMSO-d₆) δ −56.89, −112.20, −112.22 ppm.

Example 1534-[[2-(3,4-difluoro-2-methyl-phenoxy)-5-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(361)

To a solution of2-(3,4-difluoro-2-methyl-phenoxy)-5-(trifluoromethyl)benzoic acid (150mg, 0.452 mmol) in dichloromethane (5 mL) at 0° C. was added a solutionof oxalyl chloride (4.0 mL of 2.0 M in dichloromethane, 8.0 mmol)followed by DMF (50 μL). The mixture was allowed to come to roomtemperature over 1 hour, then concentrated in vacuo. The residue wasdissolved in dichloromethane (5 mL) and treated with DIEA (500 μL, 2.87mmol) then methyl 4-aminopyridine-2-carboxylate (150 mg, 0.988 mmol).The mixture was stirred at room temperature for 20 hours, then purifieddirectly by silica gel chromatography (0-100% ethyl acetate/hexanes) toprovide methyl4-[[2-(3,4-difluoro-2-methyl-phenoxy)-5-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxylate(100.2 mg, 48%). ESI-MS m z calc. 466.10, found 467.142 (M+1)⁺; LC/MSretention time: 1.41 minutes (Method B).

The solid was dissolved in a solution of ammonia in methanol (3 mL, 7 M,21 mmol) and stirred for approximately 72 hours. The mixture wasconcentrated in vacuo to provide4-[[2-(3,4-difluoro-2-methyl-phenoxy)-5-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(60.5 mg, 29%). ESI-MS m z calc.

451.10, found 452.1 (M+1)⁺; LC/MS retention time: 2.34 minutes (MethodC). ¹H NMR (400 MHz, DMSO-d₆) δ 11.10 (s, 1H), 8.54 (d, J=5.5 Hz, 1H),8.33 (s, 1H), 8.09 (dd, J=7.0, 2.6 Hz, 2H), 7.86 (dd, J=5.5, 2.1 Hz,1H), 7.83 (dd, J=8.8, 2.3 Hz, 1H), 7.64 (s, 1H), 7.37 (q, J=9.4 Hz, 1H),7.09-7.00 (m, 1H), 6.98 (d, J=8.7 Hz, 1H), 2.12 (d, J=2.3 Hz, 3H) ppm.

Example 1544-[[2-fluoro-4-methoxy-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-methyl-benzoyl]amino]pyridine-2-carboxamide(362)

Step 1: methyl 6-bromo-2,4-difluoro-3-methyl-benzoate

To a mixture of 6-bromo-2,4-difluoro-3-methyl-benzoic acid (1.0 g, 3.0mmol) in DMF (3.7 mL) was added Cs₂CO₃ (1.85 g, 5.68 mmol). The mixturewas stirred for 5 minutes at room temperature, then treated with methyliodide (809 mg, 0.355 mL, 5.70 mmol) and stirred for 1 hour. The mixturewas diluted with ethyl acetate (50 mL) and washed with aqueous NH₄Clsolution (20 mL), water (75 mL) and brine. The organic layer was driedover Na₂SO₄, filtered and concentrated to provide methyl6-bromo-2,4-difluoro-3-methyl-benzoate (900 mg, 85%). ESI-MS m z calc.263.96, found 264.9 (M+1)⁺; LC/MS retention time (Method N): 5.69minutes. ¹H NMR (250 MHz, CDCl₃) δ 7.17-7.08 (m, 1H), 3.95 (s, 3H), 2.16(td, J=2.0, 0.4 Hz, 3H) ppm.

Step 2: methyl 6-bromo-2-fluoro-4-methoxy-3-methyl-benzoate

To a solution of methyl 6-bromo-2,4-difluoro-3-methyl-benzoate (10.39 g,39.20 mmol) in anhydrous methanol (37 mL) was added 18-Crown-6 (20.8 g,78.7 mmol) followed by solid NaOMe (3.18 g, 58.7 mmol) under nitrogen.The mixture was heated at 62° C. for 21 hours, then cooled in an icebath and diluted with saturated aqueous NH₄Cl solution (50 mL). Themixture was concentrated in vacuo to remove the methanol, then dilutedwith ethyl acetate (300 mL) and washed with water (700 mL). The aqueouslayer was extracted with additional ethyl acetate (200 mL), and thecombined extracts dried over Na₂SO₄, filtered and concentrated in vacuoto provide methyl 6-bromo-2-fluoro-4-methoxy-3-methyl-benzoate (10.44 g,82%) as a yellow oil. ¹H NMR (500 MHz, CDCl₃) δ 6.84 (d, J=1.6 Hz, 1H),3.93 (s, 3H), 3.85 (s, 3H), 2.07 (d, J=2.3 Hz, 3H) ppm.

Step 3: 6-bromo-2-fluoro-4-methoxy-3-methyl-benzoic acid

Methyl 6-bromo-2-fluoro-4-methoxy-3-methyl-benzoate (5.0 g, 12.6 mmol)in a 1:1:1 mixture of methanol/water/THF (45 mL) was treated with LiOHhydrate (5.35 g, 128 mmol) and stirred at room temperature for 24 hours.Additional LiOH hydrate (3.23 g, 77.0 mmol) and 1:1:1 methanol/water/THF(45 mL) were added and the mixture stirred for 12 hours. LiOH hydrate(1.0 g, 24 mmol) and 1:1:1 methanol/water/THF (45 mL) were again addedand the mixture stirred at room temperature 12 hours. The mixture wasdiluted with saturated aqueous NH₄Cl (50 mL) and concentrated to removethe volatiles. The remaining aqueous mixture was then diluted with 1 Maqueous NaOH (200 mL) and washed with ethyl acetate, then acidified with3 M aqueous HCl (until pH=2) and extracted with ethyl acetate (3×300mL). The combined organic layers were washed with brine, dried overNa₂SO₄, filtered and concentrated in vacuo. The resulting solid wasdried 42° C. at 16 Torr for 6 hours to provide6-bromo-2-fluoro-4-methoxy-3-methyl-benzoic acid (3.87 g, 95%) as anoff-white solid. ESI-MS m z calc. 261.96, found 262.9 (M+1)⁺; LC/MSretention time (Method N): 4.43 minutes. ¹H NMR (500 MHz, DMSO-d₆) δ13.64 (s, 1H), 7.11 (d, J=1.5 Hz, 1H), 3.86 (s, 3H), 2.02 (d, J=2.1 Hz,3H) ppm.

Step 4:2-fluoro-4-methoxy-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-methyl-benzoicacid

A mixture of 6-bromo-2-fluoro-4-methoxy-3-methyl-benzoic acid (1.31 g,4.98 mmol), Cs2CO3 (4.87 g, 15.0 mmol),2-methoxy-4-(trifluoromethoxy)phenol (1.56 g, 7.50 mmol) and pyridine(822 mg, 0.840 mL, 10.4 mmol) in toluene (9 mL) was sparged withnitrogen gas for 10 minutes, and then copper (I) iodide (142.3 mg,0.7472 mmol) added and the mixture degassed for an additional 3 minutes.The reaction vessel was sealed and heated in a microwave reactor at 130°C. for 1.5 hours under nitrogen. This reaction was performed on the samescale two additional times and the crude reaction mixtures combined. Thecombined mixture was acidified with 3 M aqueous HCl (until pH=1) andextracted with ethyl acetate (3×200 mL). The combined extracts werewashed with brine, dried over Na₂SO₄, filtered and concentrated invacuo. Purification by silica gel chromatography (10-50% ethylacetate/hexanes, column pre-equilibrated with 0.1% acetic acid inhexanes), followed by additional purification by reverse phase HPLC(45-90% acetonitrile+0.1% TFA/water+0.1% TFA) provided2-fluoro-4-methoxy-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-methyl-benzoicacid (1.06 g, 18%) as a white solid. ESI-MS m z calc. 390.07, found391.4 (M+1)⁺; LC/MS retention time (Method Q): 2.59 minutes. ¹H NMR (500MHz, DMSO-d₆) δ 13.12 (s, 1H), 7.16 (d, J=2.5 Hz, 1H), 7.01-6.82 (m,2H), 6.29 (s, 1H), 3.82 (s, 3H), 3.69 (s, 3H), 2.03 (d, J=2.0 Hz, 3H)ppm.

Step 5:4-[[2-fluoro-4-methoxy-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-methyl-benzoyl]amino]pyridine-2-carboxamide(362)

A mixture of2-fluoro-4-methoxy-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-methyl-benzoicacid (300 mg, 0.769 mmol) and DMF (5 μL) in 2-MeTHF (5 mL) at 0° C. wastreated with oxalyl chloride (150 μL, 1.72 mmol) slowly over 5 minutes.The mixture was allowed to warm to room temperature over 1 hour. Themixture was concentrated in vacuo, then diluted and evaporated twicewith dichloromethane. The residue was dissolved in 2-MeTHF (5 mL) andmethyl 4-aminopyridine-2-carboxylate (120 mg, 0.789 mmol) added. NMP (2mL) was added to ensure complete dissolution of the solid. A solution ofK₂CO₃ (350 mg, 2.53 mmol) in water (5 mL) was added and the mixturestirred vigorously for 4 hours. The layers were separated and theaqueous layer extracted with ethyl acetate (2×). The combined organicextracts were dried over Na₂SO₄, filtered and concentrated in vacuo. Theresidue was dissolved in a solution of ammonia in methanol (2 mL of 7 M,14 mmol) and stirred for 66 hours. The mixture was concentrated in vacuoand purified by reverse phase HPLC (38-53% acetonitrile/0.1% ammoniumhydroxide) to provide4-[[2-fluoro-4-methoxy-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-methyl-benzoyl]amino]pyridine-2-carboxamide(87.9 mg, 22%) as a white solid. ESI-MS m z calc. 509.12, found 510.0(M+1)⁺; 508.0 (M−1)⁻; LC/MS retention time (Method E): 3.14 minutes. ¹HNMR (500 MHz, DMSO-d₆) δ 11.02 (s, 1H), 8.48 (d, J=5.6 Hz, 1H), 8.25 (d,J=2.0 Hz, 1H), 8.05 (d, J=2.8 Hz, 1H), 7.77 (d, J=5.2 Hz, 1H), 7.60 (d,J=2.9 Hz, 1H), 7.10 (dd, J=5.8, 3.0 Hz, 2H), 6.91 (ddd, J=8.9, 2.8, 1.2Hz, 1H), 6.34 (s, 1H), 3.74 (s, 3H), 3.72 (s, 3H), 2.06 (d, J=1.8 Hz,3H) ppm. ¹⁹F NMR (471 MHz, DMSO-d₆) δ −56.94, −118.56 ppm.

Example 1554-[[2-chloro-4-methoxy-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-methyl-benzoyl]amino]pyridine-2-carboxamide(363)

Step 1: 1-(2-chloro-4-methoxy-3-methyl-phenyl)ethanone

A slurry of 1-chloro-3-methoxy-2-methyl-benzene (15.0 g, 12.9 mL, 95.8mmol) and aluminum trichloride (26.2 g, 197 mmol) in dichloromethane wascooled to 10° C. and treated dropwise with acetylchloride (15.4 g, 14.0mL, 196 mmol) over 22 min. The cold bath was removed after 15 minutesand the slurry was stirred for 1 hour at room temperature. The reactionmixture was poured into 1 M aqueous HCl (400 mL) and diluted withdichloromethane (300 mL). The organic layer was separated, washed withwater (2×100 mL) and filtered through Celite. The filtrate was driedover Na₂SO₄, filtered and concentrated to provide1-(2-chloro-4-methoxy-3-methyl-phenyl)ethanone (18.24 g, 94%) which wasused without additional purification. ESI-MS m z calc. 198.05, found199.0 (M+1)⁺; LC/MS retention time (Method N): 4.94 minutes. ¹H NMR (250MHz, CDCl₃) δ 7.45 (dd, J=8.6, 0.6 Hz, 1H), 7.08-6.30 (m, 1H), 3.87 (s,3H), 2.61 (s, 3H), 2.29 (s, 3H) ppm.

Step 2: 2-chloro-4-methoxy-3-methyl-benzoic acid

A solution of 1-(2-chloro-4-methoxy-3-methyl-phenyl)ethanone (18.1 g,91.1 mmol) in dioxane (90.5 mL) was treated with sodium hypochlorite(475 mL of 5% w/v, 319 mmol) at room temperature dropwise over 1 hour.The mixture was vigorously stirred at room temperature for 3 hours afterthe addition was complete. The mixture was treated with conc. HCl untilpH˜1-2 and the resulting precipitate collected by filtration. The solidwas rinsed thoroughly with deionized water and dried under vacuum toprovide 2-chloro-4-methoxy-3-methyl-benzoic acid (17.2 g, 85%). Aportion of the crude product (10 g) was partially dissolved in ethylacetate (500 mL) and extracted with 1 M aqueous NaOH (4×100 mL) at 0° C.The basic aqueous phase was acidified at 0° C. with 3 M aqueous HCl(˜160 mL) until pH=1-2. The resulting precipitate was collected byfiltration and rinsed with ethyl acetate (70 mL). The solid wasdissolved in ethyl acetate (1.4 L) and washed with an aqueous solutionof Na₂S₂O₅ (10% wt/vol, 3×100 mL) and brine (100 mL). The organic phasewas dried over Na₂SO₄, filtered and concentrated to provide2-chloro-4-methoxy-3-methyl-benzoic acid (7.45 g, 75% recovery from 10g). ESI-MS m z calc. 200.02, found 200.8 (M+1)⁺; LC/MS retention time(Method N): 4.01 minutes. ¹H NMR (250 MHz, DMSO-d₆) δ 12.95 (s, 1H),7.70 (d, J=8.7 Hz, 1H), 7.03 (d, J=8.8 Hz, 1H), 3.87 (s, 3H), 2.24 (s,3H) ppm.

Step 3: 2-chloro-6-iodo-4-methoxy-3-methyl-benzoic acid

To a vessel charged with 2-chloro-4-methoxy-3-methyl-benzoic acid (6.55g, 32.7 mmol), N-iodosuccinimide (8.08 g, 35.9 mmol) and Pd(OAc)₂ (1.83g, 8.15 mmol) was added DMF (48 mL) at room temperature and open to air.The vessel was sealed and the mixture heated at 55° C. for 28 hours. Themixture was cooled in an ice bath, acidified with 1 M aqueous HCl (250mL) and extracted with ethyl acetate (3×150 mL). The combined organiclayers were extracted with 1 M aqueous NaOH (3×350 mL) and washed withhexanes (3×150 mL). The aqueous solution was acidified with 3 M aqueousHCl (500 mL) at 0° C. The resulting solid was collected by filtration,then dissolved in ethyl acetate (325 mL) and washed with aqueous Na₂S₂O₅(10% solution, 2×65 mL). The aqueous layer was extracted with additionalethyl acetate (3×50 mL), and the combined organic layers were washedwith brine, dried over Na₂SO₄, filtered and concentrated in vacuo toprovide 2-chloro-6-iodo-4-methoxy-3-methyl-benzoic acid (7.90 g, 66%).ESI-MS m z calc. 325.92, found 327.3 (M+1)⁺; LC/MS retention time(Method Q): 2.1 minutes. ¹H NMR (500 MHz, DMSO-d₆) δ 13.52 (s, 1H), 7.35(s, 1H), 3.83 (s, 3H), 2.15 (s, 3H) ppm.

Step 4:2-chloro-4-methoxy-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-methyl-benzoicacid

A mixture of Cs₂CO₃ (7.74 g, 23.8 mmol),2-chloro-6-iodo-4-methoxy-3-methyl-benzoic acid (2.56 g, 7.84 mmol),2-methoxy-4-(trifluoromethoxy)phenol (2.45 g, 11.8 mmol) in DMF (8.5 mL)and pyridine (1.3 g, 1.3 mL, 16.1 mmol) was stirred under an argonatmosphere for 3 minutes at room temperature, then treated with copper(I) iodide (134 mg, 0.704 mmol). The reaction vessel was sealed and themixture stirred at room temperature for 15 minutes, then heated at 80°C. for 12 hours. The mixture was cooled in an ice bath, acidified with 1M aqueous HCl until pH=2, and extracted with ethyl acetate (3×150 mL).The combined extracts were washed with 0.1 M aqueous HCl (3×75 mL) andbrine, dried over Na₂SO₄, filtered and concentrated in vacuo.Purification by reverse phase HPLC (40-100% acetonitrile+0.1%TFA/water+0.1% TFA) provided2-chloro-4-methoxy-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-methyl-benzoicacid (591 mg, 18%). ESI-MS m z calc. 406.04, found 407.2 (M+1)⁺; LC/MSretention time (Method Q): 2.68 minutes. ¹H NMR (500 MHz, DMSO-d₆) δ13.30 (s, 1H), 7.16 (d, J=2.5 Hz, 1H), 6.93 (d, J=8.8 Hz, 1H), 6.90(ddd, J=8.8, 2.6, 1.2 Hz, 1H), 6.42 (s, 1H), 3.82 (s, 3H), 3.67 (s, 3H),2.16 (s, 3H) ppm.

Step 5: methyl4-[[2-chloro-4-methoxy-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-methyl-benzoyl]amino]pyridine-2-carboxylate

To a solution of2-chloro-4-methoxy-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-methyl-benzoicacid (150 mg, 0.367 mmol) and DMF (5 μL, 0.07 mmol) in 2-MeTHF (4 mL) at0° C. was added oxalyl chloride (70 μL, 0.8024 mmol). The mixture waswarmed to room temperature, stirred for 30 minutes and then concentratedin vacuo. The residue was dissolved in 2-MeTHF (2 mL) and added to asolution of methyl 4-aminopyridine-2-carboxylate (65 mg, 0.43 mmol) andTEA (230 μL, 1.65 mmol) in 2-MeTHF (2 mL) at 0° C. The mixture waswarmed to room temperature and stirred for 3 hours, then heated at 50°C. for 20 hours. The mixture was diluted with water (30 mL) andextracted with ethyl acetate (30 mL). The organic layer was washed withwater (4×30 mL), dried over MgSO₄, filtered and concentrated in vacuo.Purification by silica gel chromatography (0-60% ethyl acetate/heptaneprovided methyl4-[[2-chloro-4-methoxy-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-methyl-benzoyl]amino]pyridine-2-carboxylate(52 mg, 26%). ESI-MS m z calc. 540.09, found 540.9 (M+1)⁺; 538.9 (M−1)⁻;LC/MS retention time (Method F): 1.02 minutes. ¹H NMR (500 MHz, DMSO-d₆)δ 11.11 (s, 1H), 8.57 (d, J=5.4 Hz, 1H), 8.35 (d, J=2.1 Hz, 1H), 7.76(dd, J=5.4, 2.1 Hz, 1H), 7.13-7.05 (m, 2H), 6.92 (d, J=8.3 Hz, 1H), 6.47(s, 1H), 3.87 (s, 3H), 3.74 (s, 3H), 3.72 (s, 3H), 2.21 (s, 3H) ppm.

Step 6:4-[[2-chloro-4-methoxy-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-methyl-benzoyl]amino]pyridine-2-carboxamide(363)

Methyl4-[[2-chloro-4-methoxy-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-methyl-benzoyl]amino]pyridine-2-carboxylate(52 mg, 0.096 mmol) was dissolved in a solution of ammonia in methanol(1 mL of 7 M, 7 mmol) and stirred for 20 hours. The mixture wasconcentrated in vacuo and purified by silica gel chromatography (0-80%ethyl acetate/heptane) to provide4-[[2-chloro-4-methoxy-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-methyl-benzoyl]amino]pyridine-2-carboxamide(19 mg, 37%). ESI-MS m z calc. 525.09, found 525.9 (M+1)⁺; 523.9 (M−1)⁻;LC/MS retention time (Method E): 3.49 minutes. ¹H NMR (500 MHz, DMSO-d₆)δ 11.06 (s, 1H), 8.49 (d, J=5.4 Hz, 1H), 8.28 (d, J=2.5 Hz, 1H), 8.05(d, J=2.7 Hz, 1H), 7.78 (dd, J=5.6, 2.2 Hz, 1H), 7.61 (d, J=2.8 Hz, 1H),7.13-7.06 (m, 2H), 6.92 (ddd, J=8.8, 2.7, 1.3 Hz, 1H), 6.46 (s, 1H),3.75 (s, 3H), 3.71 (s, 3H), 2.21 (s, 3H) ppm.

Example 1566-tert-butyl-N-(2-carbamoyl-4-pyridyl)-4-(2-chloro-4-fluoro-phenoxy)-2-methyl-pyridine-3-carboxamide(364)

Step 1: methyl 4-chloro-2-methyl-1-oxido-pyridin-1-ium-3-carboxylate

A solution of methyl 4-chloro-2-methyl-pyridine-3-carboxylate (590 mg,3.18 mmol) in dichloromethane (10 mL) was treated with3-chlorobenzenecarboperoxoic acid (900 mg, 3.65 mmol) and stirred for 2hours. The mixture was filtered and concentrated in vacuo to providemethyl 4-chloro-2-methyl-1-oxido-pyridin-1-ium-3-carboxylate (620 mg,97%). ESI-MS m z calc. 201.02, found 202.1 (M+1)⁺; LC/MS retention time(Method F): 0.41 minutes. The material was taken to the next stepwithout additional purification.

Step 2: methyl 6-tert-butyl-4-chloro-2-methyl-pyridine-3-carboxylate

A solution of methyl4-chloro-2-methyl-1-oxido-pyridin-1-ium-3-carboxylate (600 mg, 2.98mmol) and [Ir(ppy)₂(dtbbpy)]PF₆ (32 mg, 0.035 mmol) in acetonitrile (6mL) was treated with 2,2-dimethylpropanoyl chloride (400 μL, 3.25 mmol)and stirred for 5 minutes. The reaction vial was then sealed and themixture stirred under 450 nm LED light for 4 hours. The mixture wasconcentrated in vacuo and purified by silica gel chromatography (0-50%ethyl acetate/heptane) to provide methyl6-tert-butyl-4-chloro-2-methyl-pyridine-3-carboxylate (350 mg, 49%).ESI-MS m z calc. 241.09, found 242.2 (M+1)⁺; LC/MS retention time(Method F): 1.04 minutes. ¹H NMR (400 MHz, CDCl₃) δ 7.19 (d, J=0.7 Hz,1H), 3.95 (s, 3H), 2.53 (d, J=0.5 Hz, 3H), 1.32 (s, 9H) ppm.

Step 3:6-tert-butyl-4-(2-chloro-4-fluoro-phenoxy)-2-methyl-pyridine-3-carboxylicacid

A solution of methyl6-tert-butyl-4-chloro-2-methyl-pyridine-3-carboxylate (350 mg, 1.45mmol) in acetonitrile (3 mL) was treated with Cs₂CO₃ (600 mg, 1.84 mmol)and 2-chloro-4-fluoro-phenol (170 μL, 1.56 mmol) and stirred at roomtemperature for 4 hours. Aqueous LiOH (3.5 mL of 2 M, 7 mmol) andethanol (3 mL) were added and the mixture stirred at room temperaturefor 3 days. The mixture was diluted with ethyl acetate and washed with 2M aqueous NaOH. The organic layer was dried over MgSO₄, filtered andconcentrated to provide crude methyl6-tert-butyl-4-(2-chloro-4-fluoro-phenoxy)-2-methyl-pyridine-3-carboxylate.Aqueous LiOH (3.5 mL of 2 M, 7 mmol) and ethanol (3 mL) were added andthe mixture stirred to afford the hydrolyzed ester. The mixture wasacidified with 2 M aqueous HCl (6 mL) and extracted into ethyl acetate.The organic layer was separated, dried over MgSO₄ and concentrated toprovide6-tert-butyl-4-(2-chloro-4-fluoro-phenoxy)-2-methyl-pyridine-3-carboxylicacid (350 mg, 72%). ESI-MS m z calc. 337.09, no ionization observed;LC/MS retention time (Method F): 0.59 minutes.

Step 4: methyl4-[[6-tert-butyl-4-(2-chloro-4-fluoro-phenoxy)-2-methyl-pyridine-3-carbonyl]amino]pyridine-2-carboxylate

To a solution of6-tert-butyl-4-(2-chloro-4-fluoro-phenoxy)-2-methyl-pyridine-3-carboxylicacid (50 mg, 0.15 mmol) in dichloromethane (2 mL) cooled to 0° C. wasadded DMF (2 μL, 0.03 mmol) followed by oxalyl chloride (50 μL, 0.57mmol). The mixture was allowed to warm to room temperature over 1 hour,then concentrated in vacuo. The residue was dissolved in dichloromethane(2 mL), cooled in an ice bath, and TEA (50 μL, 0.36 mmol) and methyl4-aminopyridine-2-carboxylate (30 mg, 0.20 mmol) added sequentially. Themixture was stirred for 16 hours. The mixture was filtered (0.45 Mfilter), diluted with 3:1 acetonitrile/water and purified directly byreverse phase HPLC (47-95% acetonitrile/0.1% ammonium hydroxide) toprovide methyl4-[[6-tert-butyl-4-(2-chloro-4-fluoro-phenoxy)-2-methyl-pyridine-3-carbonyl]amino]pyridine-2-carboxylate(20 mg, 29%). ESI-MS m z calc. 471.14, found 472.4 (M+1)⁺; 470.3 (M−1)+;LC/MS retention time (Method F): 0.97 minutes.

Step 5:6-tert-butyl-N-(2-carbamoyl-4-pyridyl)-4-(2-chloro-4-fluoro-phenoxy)-2-methyl-pyridine-3-carboxamide(364)

Methyl4-[[6-tert-butyl-4-(2-chloro-4-fluoro-phenoxy)-2-methyl-pyridine-3-carbonyl]amino]pyridine-2-carboxylate(20 mg, 0.042 mmol) was dissolved in a solution of ammonia in methanol(2 mL of 7 M, 14 mmol) and stirred in a sealed vial at 40° C. for 16hours. The solvent was removed in vacuo to provide6-tert-butyl-N-(2-carbamoyl-4-pyridyl)-4-(2-chloro-4-fluoro-phenoxy)-2-methyl-pyridine-3-carboxamide(10.9 mg, 55%). ESI-MS m z calc. 456.14, found 457.2 (M+1)⁺; 455.2(M−1)⁻; LC/MS retention time (Method E): 3.14 minutes. ¹H NMR (400 MHz,CDCl₃) δ 9.50 (s, 1H), 8.56-8.40 (m, 2H), 8.22-8.10 (m, 1H), 7.76 (d,J=4.7 Hz, 1H), 7.22 (dd, J=7.9, 3.0 Hz, 1H), 7.21-7.16 (m, 1H), 7.04(ddd, J=9.0, 7.5, 3.0 Hz, 1H), 6.38 (s, 1H), 5.18 (d, J=4.7 Hz, 1H),2.65 (s, 3H), 1.25 (s, 9H) ppm.

Example 1574-[[6-(2-chloro-4-fluoro-phenoxy)-2-fluoro-4-methoxy-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(6M5)

Step 1:6-(2-chloro-4-fluoro-phenoxy)-2-fluoro-4-methoxy-3-(trifluoromethyl)benzoicacid

A mixture of 6-bromo-2-fluoro-4-methoxy-3-(trifluoromethyl)benzoic acid(3.0 g, 9.5 mmol, see US 2019/0016671, Example 129, Step 3, which isincorporated by reference), 2-chloro-4-fluoro-phenol (1.57 g, 1.17 mL,10.7 mmol), Cs₂CO₃ (3.37 g, 10.3 mmol) and copper iodide (395 mg, 2.07mmol) was flushed with nitrogen before adding in toluene (60 mL). Themixture was stirred at 100° C. under nitrogen for 2 hours. The cooledmixture was acidified with 1 M aqueous HCl, then diluted with water andethyl acetate. The layers were separated and the aqueous layer wasextracted with ethyl acetate (2×60 mL). The combined organic layers werewashed with brine, dried over MgSO₄, filtered, and concentrated invacuo. Purification by silica gel chromatography (0-60% ethylacetate/heptane) provided6-(2-chloro-4-fluoro-phenoxy)-2-fluoro-4-methoxy-3-(trifluoromethyl)benzoicacid (2.94 g, 81%). ¹H NMR (400 MHz, CDCl₃) δ 7.30-7.27 (m, 1H), 7.17(dd, J=9.0, 5.0 Hz, 1H), 7.07 (ddd, J=9.0, 7.4, 3.0 Hz, 1H), 5.97 (s,1H), 3.72 (s, 3H) ppm. ESI-MS m z calc. 382.00, LC/MS retention time(Method F): 0.96 minutes.

Step 2: methyl4-[[6-(2-chloro-4-fluoro-phenoxy)-2-fluoro-4-methoxy-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxylate

A solution of6-(2-chloro-4-fluoro-phenoxy)-2-fluoro-4-methoxy-3-(trifluoromethyl)benzoicacid (280 mg, 0.732 mmol) in dichloromethane (14 mL) at 0° C. wastreated with oxalyl chloride (210 μL, 2.41 mmol) followed by addition ofDMF (5 μL, 0.07 mmol). The resulting mixture was stirred for 1 hour,then treated with additional oxalyl chloride (100 μL) and DMF (2 drops).The mixture was stirred at room temperature for 3 hours thenconcentrated in vacuo. The residue was dissolved in dichloromethane (14mL), cooled to 0° C., and then treated with methyl4-aminopyridine-2-carboxylate (120 mg, 0.789 mmol) and TEA (210 μL, 1.51mmol). The mixture was allowed to warm to room temperature and stirredovernight. The mixture was concentrated in vacuo and purified by silicagel chromatography (0-100% ethyl acetate/heptane) to provide methyl4-[[6-(2-chloro-4-fluoro-phenoxy)-2-fluoro-4-methoxy-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxylate(215 mg, 57%). ESI-MS m z calc. 516.05, found 517.1 (M+1)⁺; 515.1(M−1)⁻; LC/MS retention time (Method F): 0.9 minutes. ¹H NMR (400 MHz,CDCl₃) δ 8.68 (d, J=5.5 Hz, 1H), 8.24 (s, 1H), 8.16 (d, J=2.2 Hz, 1H),8.08-8.04 (m, 1H), 7.30 (dd, J=7.8, 2.9 Hz, 1H), 7.23 (d, J=5.0 Hz, 1H),7.11 (ddd, J=9.0, 7.4, 3.0 Hz, 1H), 5.98 (s, 1H), 4.01 (s, 3H), 3.73 (s,3H) ppm.

Step 3:4-[[6-(2-chloro-4-fluoro-phenoxy)-2-fluoro-4-methoxy-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(365)

Methyl4-[[6-(2-chloro-4-fluoro-phenoxy)-2-fluoro-4-methoxy-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxylate(215 mg, 0.416 mmol) was dissolved in a solution of ammonia in methanol(5 mL of 7 M, 35 mmol) and stirred overnight. The mixture wasconcentrated in vacuo and by reverse phase HPLC (47-95%acetonitrile/0.1% ammonium hydroxide) to provide4-[[6-(2-chloro-4-fluoro-phenoxy)-2-fluoro-4-methoxy-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(66.5 mg, 32%). ESI-MS m z calc. 501.05, found 502.1 (M+1)⁺; 500.1(M−1)⁻; LC/MS retention time (Method E): 3.04 minutes. H NMR (400 MHz,DMSO-d₆) δ 11.26 (s, 1H), 8.53 (d, J=5.5 Hz, 1H), 8.26 (d, J=2.2 Hz,1H), 8.08 (s, 1H), 7.79 (dd, J=5.6, 2.2 Hz, 1H), 7.63 (dd, J=8.3, 3.0Hz, 2H), 7.42 (dd, J=9.1, 5.1 Hz, 1H), 7.32 (ddd, J=9.2, 8.0, 3.1 Hz,1H), 6.46 (s, 1H), 3.81 (s, 3H) ppm.

Example 1585-[[6-(2-chloro-4-fluoro-phenoxy)-2-fluoro-4-methoxy-3-(trifluoromethyl)benzoyl]amino]pyrimidine-2-carboxamide(366)

This compound was made in an analogous fashion to the synthesis ofcompound 365 in Example 157, except employing methyl5-aminopyrimidine-2-carboxylate for the amide formation step to providemethyl5-[[6-(2-chloro-4-fluoro-phenoxy)-2-fluoro-4-methoxy-3-(trifluoromethyl)benzoyl]amino]pyrimidine-2-carboxylate(30 mg, 10%). ¹H NMR (400 MHz, CDCl₃) δ 9.25 (s, 2H), 8.07 (s, 1H), 7.32(dd, J=7.7, 2.9 Hz, 1H), 7.24-7.20 (m, 1H), 7.16-7.09 (m, 1H), 6.05 (s,1H), 4.07 (s, 3H), 3.75 (s, 3H) ppm. ESI-MS m z calc. 517.05, found518.1 (M+1)⁺; 516.1 (M−1)⁻; LC/MS retention time (Method F): 0.86minutes.

Analogous treatment with methanolic ammonia provided5-[[6-(2-chloro-4-fluoro-phenoxy)-2-fluoro-4-methoxy-3-(trifluoromethyl)benzoyl]amino]pyrimidine-2-carboxamide(10.4 mg, 38%). ESI-MS m/z calc. 502.05, found 503.1 (M+1)⁺; 501.1(M−1)⁻; LC/MS retention time (Method E): 2.8 minutes. ¹H NMR (400 MHz,DMSO-d₆) δ 11.40 (s, 1H), 9.11 (s, 2H), 8.11 (s, 1H), 7.71 (s, 1H), 7.63(dd, J=8.3, 3.0 Hz, 1H), 7.40 (dd, J=9.1, 5.1 Hz, 1H), 7.31 (td, J=9.0,8.6, 3.0 Hz, 1H), 6.51 (s, 1H), 3.82 (s, 3H) ppm.

Example 1595-[[6-(2-chloro-4-fluoro-phenoxy)-2-fluoro-4-methoxy-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(367)

This compound was made in an analogous fashion to the synthesis ofcompound 365 in Example 157, above, except employing5-aminopyridine-2-carboxamide in the amide coupling step to provide5-[[6-(2-chloro-4-fluoro-phenoxy)-2-fluoro-4-methoxy-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(93.8 mg, 23%). ¹H NMR (400 MHz, DMSO-d₆) δ 11.19 (s, 1H), 8.80 (d,J=2.4 Hz, 1H), 8.23 (dd, J=8.6, 2.5 Hz, 1H), 8.07-7.97 (m, 2H), 7.63(dd, J=8.4, 3.0 Hz, 1H), 7.55 (s, 1H), 7.41 (dd, J=9.1, 5.2 Hz, 1H),7.31 (ddd, J=9.1, 8.0, 3.0 Hz, 1H), 6.49 (s, 1H), 3.82 (s, 3H) ppm.ESI-MS m z calc. 501.05, found 502.1 (M+1)⁺; 500.1 (M−1)⁻; LC/MSretention time (Method E): 2.97 minutes.

Example 1604-[[6-[2-chloro-4-(trifluoromethoxy)phenoxy]-2-fluoro-4-methoxy-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(368)

Step 1:6-[2-chloro-4-(trifluoromethoxy)phenoxy]-2-fluoro-4-methoxy-3-(trifluoromethyl)benzoicacid

A mixture of 6-bromo-2-fluoro-4-methoxy-3-(trifluoromethyl)benzoic acid(502 mg, 1.58 mmol, see US 2019/0016671, Example 129, Step 3, which isincorporated by reference), 2-chloro-4-(trifluoromethoxy)phenol (400 mg,1.88 mmol) and Cs₂CO₃ (600 mg, 1.84 mmol) in toluene (10 mL) was bubbledwith nitrogen for 10 minutes, then treated with copper (I) iodide (72mg, 0.38 mmol). The mixture was stirred at 100° C. for 3 hours. Thecooled mixture was acidified with 1 M aqueous HCl, then diluted withwater and ethyl acetate. The layers were separated and the aqueous layerwas extracted with additional ethyl acetate (2×30 mL). The combinedorganic extracts were washed with brine, dried over MgSO₄, filtered andconcentrated in vacuo. Purification by silica gel chromatography (0-100%ethyl acetate/heptane) provided6-[2-chloro-4-(trifluoromethoxy)phenoxy]-2-fluoro-4-methoxy-3-(trifluoromethyl)benzoicacid (625 mg, 88%). ESI-MS m z calc. 448.00, no ionization observed;LC/MS retention time (Method F): 0.6 minutes. ¹H NMR (400 MHz, CDCl₃) δ7.42 (d, J=2.6 Hz, 1H), 7.24-7.18 (m, 1H), 7.18-7.14 (m, 1H), 6.06 (s,1H), 3.76 (s, 3H) ppm.

Step 2: methyl4-[[6-[2-chloro-4-(trifluoromethoxy)phenoxy]-2-fluoro-4-methoxy-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxylate

A solution of6-[2-chloro-4-(trifluoromethoxy)phenoxy]-2-fluoro-4-methoxy-3-(trifluoromethyl)benzoicacid (301 mg, 0.671 mmol) in dichloromethane (6 mL) at 0° C. was treatedwith oxalyl chloride (193 μL, 2.21 mmol) followed by addition of DMF (5μL, 0.07 mmol). The resulting mixture was stirred for 15 minutes at 0°C., then allowed to warm to room temperature over 1 hour. The mixturewas concentrated in vacuo. The residue was dissolved in dichloromethane(6 mL), cooled in an ice bath, and treated with methyl4-aminopyridine-2-carboxylate (124 mg, 0.815 mmol) and TEA (217 μL, 1.56mmol). The mixture was allowed to warm to room temperature and stirredovernight. The mixture was concentrated in vacuo and purified by silicagel chromatography (0-100% ethyl acetate/heptane) to provide methyl4-[[6-[2-chloro-4-(trifluoromethoxy)phenoxy]-2-fluoro-4-methoxy-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxylate(40 mg, 8%). ESI-MS m z calc. 582.045, found 583.0 (M+1)⁺; 581.1 (M−1)⁻;LC/MS retention time (Method F): 0.96 minutes. ¹H NMR (400 MHz, CDCl₃) δ8.65 (d, J=5.5 Hz, 1H), 8.40-8.28 (m, 1H), 8.13 (d, J=2.3 Hz, 1H), 8.01(dd, J=5.5, 2.2 Hz, 1H), 7.42 (dq, J=1.6, 0.9 Hz, 1H), 7.23 (d, J=1.5Hz, 2H), 6.04 (d, J=1.5 Hz, 1H), 3.98 (s, 3H), 3.75 (s, 3H) ppm.

Step 3:4-[[6-[2-chloro-4-(trifluoromethoxy)phenoxy]-2-fluoro-4-methoxy-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(369)

Methyl4-[[6-[2-chloro-4-(trifluoromethoxy)phenoxy]-2-fluoro-4-methoxy-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxylate(38 mg, 0.06520 mmol) was dissolved in a solution of ammonia in methanol(1 mL of 7 M, 7 mmol) and stirred for approximately 72 hours. Themixture was concentrated in vacuo and purified by reverse phase HPLC(47-95% acetonitrile/0.1% ammonium hydroxide) to provide4-[[6-[2-chloro-4-(trifluoromethoxy)phenoxy]-2-fluoro-4-methoxy-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(8.4 mg, 22%). ESI-MS m z calc. 567.04, found 568.0 (M+1)⁺; LC/MSretention time (Method E): 3.32 minutes. ¹H NMR (400 MHz, DMSO-d₆) δ8.50 (d, J=5.4 Hz, 1H), 8.21 (d, J=2.1 Hz, 1H), 7.96 (s, 1H), 7.73 (dd,J=5.5, 2.2 Hz, 1H), 7.65 (d, J=1.9 Hz, 1H), 7.46 (s, 1H), 7.39 (d, J=1.5Hz, 2H), 6.67 (s, 1H), 3.85 (s, 3H) ppm.

Example 1615-[[6-[2-chloro-4-(trifluoromethoxy)phenoxy]-2-fluoro-4-methoxy-3-(trifluoromethyl)benzoyl]amino]pyrimidine-2-carboxamide(369)

This compound was made in an analogous fashion to the synthesis ofcompound 368 in Example 160, except employing methyl5-aminopyrimidine-2-carboxylate for the amide formation step (Step 2).The yield of methyl5-[[6-[2-chloro-4-(trifluoromethoxy)phenoxy]-2-fluoro-4-methoxy-3-(trifluoromethyl)benzoyl]amino]pyrimidine-2-carboxylatewas 70 mg (23%). ESI-MS m z calc. 583.04, found 584.1 (M+1)⁺; 582.1(M−1)⁻; LC/MS retention time (Method F): 0.95 minutes. ¹H NMR (400 MHz,CDCl₃) δ 9.24 (s, 2H), 8.04 (s, 1H), 7.45 (dd, J=2.2, 1.1 Hz, 1H), 7.25(s, 1H), 6.08 (s, 1H), 4.07 (s, 3H), 3.78 (s, 3H) ppm.

Analogous treatment with methanolic ammonia provided5-[[6-[2-chloro-4-(trifluoromethoxy)phenoxy]-2-fluoro-4-methoxy-3-(trifluoromethyl)benzoyl]amino]pyrimidine-2-carboxamide(12.2 mg, 17%). ¹H NMR (400 MHz, DMSO-d₆) δ 11.40 (s, 1H), 9.07 (s, 2H),8.10 (s, 1H), 7.72 (s, 2H), 7.40 (d, J=7.1 Hz, 2H), 6.78 (s, 1H), 3.88(s, 3H). ESI-MS m z calc. 568.04, found 569.1 (M+1)⁺; 567.0 (M−1)⁻;LC/MS retention time (Method E): 3.11 minutes.

Example 1625-[[6-[2-chloro-4-(trifluoromethoxy)phenoxy]-2-fluoro-4-methoxy-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(370)

This compound was made in an analogous fashion to the synthesis ofcompound 368 in Example 160, except employing5-aminopyridine-2-carboxamide for the amide formation step (Step 2). Theyield of5-[[6-[2-chloro-4-(trifluoromethoxy)phenoxy]-2-fluoro-4-methoxy-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamidewas 49.1 mg (12%). ESI-MS m z calc. 567.04, found 568.0 (M+1)⁺; 566.1(M−1)+; LC/MS retention time (Method E): 3.26 minutes. ¹H NMR (400 MHz,DMSO-d₆) δ 11.18 (s, 1H), 8.75 (dd, J=2.5, 0.7 Hz, 1H), 8.17 (dd, J=8.6,2.5 Hz, 1H), 8.08-7.91 (m, 2H), 7.72 (d, J=2.7 Hz, 1H), 7.54 (s, 1H),7.44-7.40 (m, 1H), 7.38 (d, J=9.0 Hz, 1H), 6.77 (s, 1H), 3.87 (s, 3H)ppm.

Example 1634-[[2-(3,4-difluoro-2-methoxy-phenoxy)-4-fluoro-6-methyl-benzoyl]amino]pyridine-2-carboxamide(371)

Step 1: 2-(3,4-difluoro-2-methoxy-phenoxy)-4-fluoro-6-methyl-benzoicacid

2-Bromo-4-fluoro-6-methyl-benzoic acid (1.5 g, 6.4 mmol) and Cs₂CO₃ (2.4g, 7.4 mmol) were suspended in toluene (15 mL). The mixture was treatedwith copper (I) iodide (240 mg, 1.26 mmol) and3,4-difluoro-2-methoxy-phenol (1.0 g, 6.25 mmol) then heated in a sealedreaction vial at 100° C. for 3 hours. The cooled mixture was dilutedwith ethyl acetate (5 mL) and acidified with 1 M aqueous HCl (˜5 mL) topH=1. The aqueous layer was extracted with additional ethyl acetate (2×5mL), and the combined extracts dried over Na₂SO₄, filtered andconcentrated in vacuo. Purification by silica gel chromatography (0-80%ethyl acetate/heptane), followed by a second silica gel chromatographypurification (10-60% ethyl acetate/heptane) provided2-(3,4-difluoro-2-methoxy-phenoxy)-4-fluoro-6-methyl-benzoic acid (547mg, 27%). ¹H NMR (500 MHz, DMSO-d₆) δ 13.30 (s, 1H), 7.19 (td, J=9.8,8.5 Hz, 1H), 6.99-6.86 (m, 2H), 6.51 (dd, J=10.2, 2.3 Hz, 1H), 3.90-3.82(m, 3H), 2.33 (s, 3H) ppm.

Step 2: methyl4-[[2-(3,4-difluoro-2-methoxy-phenoxy)-4-fluoro-6-methyl-benzoyl]amino]pyridine-2-carboxylate

A solution of2-(3,4-difluoro-2-methoxy-phenoxy)-4-fluoro-6-methyl-benzoic acid (270mg, 0.865 mmol) and DMF (5 μL) in dichloromethane (5 mL) at 0° C. wastreated dropwise with oxalyl chloride (150 μL, 1.72 mmol) and stirredfor stirred for 1 hour. The mixture was concentrated in vacuo, thendiluted and evaporated twice with dichloromethane. The residue wasdissolved in dichloromethane (1 mL) and added to a solution of methyl4-aminopyridine-2-carboxylate (130 mg, 0.854 mmol) and TEA (500 μL, 3.59mmol) in dichloromethane (5 mL) at 0° C. The mixture was allowed to warmto room temperature and stirred for 18 hours. The mixture was dilutedwith water with water (1 mL) and the phases separated. The organic phasewas concentrated and purified by silica gel chromatography (0-70% ethylacetate/heptane) to provide methyl4-[[2-(3,4-difluoro-2-methoxy-phenoxy)-4-fluoro-6-methyl-benzoyl]amino]pyridine-2-carboxylate(107 mg, 28%) as an orange oil. ESI-MS m z calc. 446.11, found 447.0(M+1)⁺; 445.0 (M−1)⁻; LC/MS retention time (Method F): 0.87 minutes. ¹HNMR (500 MHz, DMSO-d₆) δ 11.17 (s, 1H), 8.60 (d, J=5.4 Hz, 1H), 8.43 (d,J=2.0 Hz, 1H), 7.84 (dd, J=5.4, 2.1 Hz, 1H), 7.22 (td, J=9.9, 8.5 Hz,1H), 7.05-6.97 (m, 2H), 6.56 (dd, J=10.2, 2.4 Hz, 1H), 3.88 (s, 3H),3.83 (d, J=1.0 Hz, 3H), 2.35 (s, 3H) ppm. ¹⁹F NMR (471 MHz, DMSO-d₆) δ−109.38, −139.86 (d, J=21.7 Hz), −152.46 (d, J=21.1 Hz) ppm.

Step 3:4-[[2-(3,4-difluoro-2-methoxy-phenoxy)-4-fluoro-6-methyl-benzoyl]amino]pyridine-2-carboxamide(371)

Methyl4-[[2-(3,4-difluoro-2-methoxy-phenoxy)-4-fluoro-6-methyl-benzoyl]amino]pyridine-2-carboxylate(107 mg, 0.2397 mmol) was dissolved in a solution of ammonia in methanol(1 mL of 7 M, 7 mmol) and stirred for 18 hours. The mixture wasconcentrated in vacuo and the residue purified by reverse phase HPLC(47-95% acetonitrile/0.1% ammonium hydroxide) to provide4-[[2-(3,4-difluoro-2-methoxy-phenoxy)-4-fluoro-6-methyl-benzoyl]amino]pyridine-2-carboxamide(24.3 mg, 23%) as a white solid. ESI-MS m z calc. 431.11, found 432.0(M+1)⁺; 430.0 (M−1)⁻; LC/MS retention time (Method E): 2.84 minutes. ¹HNMR (500 MHz, DMSO-d₆) δ 11.11 (s, 1H), 8.51 (d, J=5.5 Hz, 1H), 8.35 (d,J=2.2 Hz, 1H), 8.06 (d, J=2.8 Hz, 1H), 7.83 (dd, J=5.5, 2.2 Hz, 1H),7.61 (d, J=2.8 Hz, 1H), 7.25-7.16 (m, 1H), 7.04-6.96 (m, 2H), 6.54 (dd,J=10.2, 2.4 Hz, 1H), 3.82 (d, J=0.8 Hz, 3H), 2.35 (s, 3H) ppm. ¹⁹F NMR(471 MHz, DMSO-d₆) δ −109.52, −139.90 (d, J=21.7 Hz), −152.49 (d, J=22.2Hz) ppm.

Example 1644-[[6-(3,4-difluoro-2-methoxy-phenoxy)-2-fluoro-4-methoxy-3-methyl-benzoyl]amino]pyridine-2-carboxamide(372)

Step 1:6-(3,4-difluoro-2-methoxy-phenoxy)-2-fluoro-4-methoxy-3-methyl-benzoicacid

6-Bromo-2-fluoro-4-methoxy-3-methyl-benzoic acid (0.5 g, 2 mmol, seeExample 154, Step 3), 3,4-difluoro-2-methoxy-phenol (300 mg, 1.87 mmol)and Cs₂CO₃ (1.2 g, 3.683 mmol) were combined in toluene (10 mL) and themixture bubbled with nitrogen for 5 minutes. The mixture was treatedwith copper (I) iodide (90 mg, 0.47 mmol) and heated in a sealed vial at100° C. for 90 minutes. The cooled mixture was then partitioned betweenethyl acetate and water, and the aqueous layer acidified to pH=1. Thelayers were separated and the aqueous layer extracted with additionalethyl acetate (2×). The combined extracts were washed with brine, driedover Na₂SO₄, filtered and concentrated in vacuo. Purification by silicagel chromatography (0-100% ethyl acetate/heptane), followed by a secondsilica gel chromatography purification (0-50% ethyl acetate/heptane)provided6-(3,4-difluoro-2-methoxy-phenoxy)-2-fluoro-4-methoxy-3-methyl-benzoicacid (279 mg, 43%). ¹H NMR (500 MHz, DMSO-d₆) δ 13.20 (s, 1H), 7.14 (td,J=9.9, 8.6 Hz, 1H), 6.77 (ddd, J=9.4, 5.0, 2.3 Hz, 1H), 6.37 (d, J=1.4Hz, 1H), 3.89 (d, J=0.8 Hz, 3H), 3.72 (s, 3H), 2.03 (d, J=2.1 Hz, 3H)ppm.

Step 2: methyl4-[[6-(3,4-difluoro-2-methoxy-phenoxy)-2-fluoro-4-methoxy-3-methyl-benzoyl]amino]pyridine-2-carboxylate

A solution of6-(3,4-difluoro-2-methoxy-phenoxy)-2-fluoro-4-methoxy-3-methyl-benzoicacid (279 mg, 0.815 mmol) and DMF (5 μL) in dichloromethane (5 mL) at 0°C. was treated dropwise with oxalyl chloride (150 μL, 1.72 mmol) andstirred for 1 hour. The mixture was concentrated in vacuo, then dilutedand evaporated twice with dichloromethane. The residue was dissolved indichloromethane (1 mL) and added to a solution of methyl4-aminopyridine-2-carboxylate (125 mg, 0.822 mmol) and TEA (500 μL, 3.59mmol) in dichloromethane (5 mL) at 0° C. The mixture was allowed to warmto room temperature and stirred for 18 hours. The mixture was dilutedwith water (1 mL) and the layers separated. The organic phase wasconcentrated and purified by silica gel chromatography (0-100% ethylacetate/heptane) to provide methyl4-[[6-(3,4-difluoro-2-methoxy-phenoxy)-2-fluoro-4-methoxy-3-methyl-benzoyl]amino]pyridine-2-carboxylate(135 mg, 35%). ESI-MS m z calc. 476.12, found 477.0 (M+1)⁺; 475.0(M−1)⁻; LC/MS retention time (Method F): 0.89 minutes. ¹H NMR (500 MHz,DMSO-d₆) δ 11.16 (s, 1H), 8.58 (d, J=5.4 Hz, 1H), 8.35 (d, J=2.0 Hz,1H), 7.79 (dd, J=5.5, 2.1 Hz, 1H), 7.16 (td, J=9.7, 8.5 Hz, 1H), 6.90(ddd, J=9.3, 5.0, 2.2 Hz, 1H), 6.38 (d, J=1.4 Hz, 1H), 3.87 (s, 3H),3.84 (d, J=0.9 Hz, 3H), 3.74 (s, 3H), 2.11-2.04 (m, 3H) ppm. ¹⁹F NMR(471 MHz, DMSO-d₆) δ −118.38, −141.00 (d, J=21.7 Hz), −152.81 (d, J=21.5Hz) ppm.

Step 3:4-[[6-(3,4-difluoro-2-methoxy-phenoxy)-2-fluoro-4-methoxy-3-methyl-benzoyl]amino]pyridine-2-carboxamide(372)

Methyl4-[[6-(3,4-difluoro-2-methoxy-phenoxy)-2-fluoro-4-methoxy-3-methyl-benzoyl]amino]pyridine-2-carboxylate(134 mg, 0.281 mmol) was dissolved in a solution of ammonia in methanol(1 mL of 7 M, 7 mmol). The mixture was stirred at room temperatureovernight. The mixture was concentrated in vacuo and purified by reversephase HPLC (47-95% acetonitrile/0.1% ammonium hydroxide) to provide4-[[6-(3,4-difluoro-2-methoxy-phenoxy)-2-fluoro-4-methoxy-3-methyl-benzoyl]amino]pyridine-2-carboxamide(23.2 mg, 18%) as a white solid. ESI-MS m z calc. 461.12, found 461.6(M+1)⁺; 460.0 (M−1)⁻; LC/MS retention time (Method E): 2.99 minutes. ¹HNMR (500 MHz, DMSO-d₆) δ 11.11 (s, 1H), 8.50 (d, J=5.5 Hz, 1H), 8.29 (d,J=2.2 Hz, 1H), 8.06 (d, J=2.9 Hz, 1H), 7.79 (dd, J=5.5, 2.2 Hz, 1H),7.62 (d, J=2.9 Hz, 1H), 7.16 (td, J=9.7, 8.4 Hz, 1H), 6.91 (ddd, J=9.4,5.0, 2.2 Hz, 1H), 6.38 (d, J=1.3 Hz, 1H), 3.84 (d, J=0.8 Hz, 3H), 3.74(s, 3H), 2.07 (d, J=1.8 Hz, 3H) ppm. ¹⁹F NMR (471 MHz, DMSO-d₆) δ−118.44, −141.00 (d, J=21.0 Hz), −152.82 (d, J=21.6 Hz) ppm.

Example 1654-[[4-chloro-6-(3,4-difluoro-2-methoxy-phenoxy)-2-fluoro-3-methyl-benzoyl]amino]pyridine-2-carboxamide(373)

Step 1: methyl4-chloro-2-(3,4-difluoro-2-methoxy-phenoxy)-6-fluoro-benzoate

A mixture of Cs₂CO₃ (2.40 g, 7.37 mmol), 3,4-difluoro-2-methoxy-phenol(819 mg, 5.12 mmol) and methyl 4-chloro-2,6-difluoro-benzoate (1.00 g,4.84 mmol) in DMF (17.5 mL) was stirred at room temperature for 21hours, then heated at 50° C. for 3 hours. The mixture was then dilutedwith ethyl acetate and washed with water (3×) and brine (2×). Theorganic layer was dried over MgSO₄, filtered and concentrated in vacuo.The residue was purified by silica gel chromatography (0-10% ethylacetate/petroleum ether) to provide methyl4-chloro-2-(3,4-difluoro-2-methoxy-phenoxy)-6-fluoro-benzoate (1.23 g,73%) as a colorless oil. ESI-MS m z calc. 346.02, no ionizationobserved; LC/MS retention time (Method F): 0.99 minutes. ¹H NMR (400MHz, CDCl₃) δ 6.97-6.83 (m, 3H), 6.47 (t, J=1.6 Hz, 1H), 3.95 (s, 3H),3.94 (d, J=1.5 Hz, 3H) ppm.

Step 2: methyl4-chloro-6-(3,4-difluoro-2-methoxy-phenoxy)-2-fluoro-3-methyl-benzoate

A solution of LDA (1.78 mL of 2 M in THF/heptane/ethylbenzene, 3.56mmol) was added dropwise to a solution of methyl4-chloro-2-(3,4-difluoro-2-methoxy-phenoxy)-6-fluoro-benzoate (1.226 g,3.536 mmol) in THF (12.0 mL) at −78° C. The mixture was stirred at thistemperature for 10 minutes then methyl iodide (335 μL, 5.38 mmol) wasadded. The mixture was stirred at −78° C. for 30 minutes then allowed towarm to room temperature. The mixture was diluted with water andextracted with ethyl acetate (3×20 mL). The combined organic extractswere dried over MgSO₄, filtered and concentrated in vacuo. The residuewas purified by silica gel chromatography (0-100% ethyl acetate/heptane)to provide methyl4-chloro-6-(3,4-difluoro-2-methoxy-phenoxy)-2-fluoro-3-methyl-benzoateas a colorless oil which was taken directly to the next step.

Step 3:4-chloro-6-(3,4-difluoro-2-methoxy-phenoxy)-2-fluoro-3-methyl-benzoicacid

To a slurry of methyl4-chloro-6-(3,4-difluoro-2-methoxy-phenoxy)-2-fluoro-3-methyl-benzoatein methanol (36 mL) and water (36 mL) was added NaOH (1.40 g, 35.0 mmol)and the mixture stirred at room temperature for approximately 72 hours.The mixture was cooled to room temperature and acidified with 2 Maqueous HCl (22 mL, 44 mmol). The volatiles were removed in vacuo andthe aqueous mixture extracted with ethyl acetate (3×). The combinedorganic extracts were dried over MgSO₄, filtered and concentrated invacuo to impure provide4-chloro-6-(3,4-difluoro-2-methoxy-phenoxy)-2-fluoro-3-methyl-benzoicacid (1.12 g, 91%). ESI-MS m z calc. 346.02, no ionization observed,LC/MS retention time (Method F): 0.58 minutes. The isolated material wastaken directly to the subsequent amide coupling step without additionalpurification.

Step 4:4-[[4-chloro-6-(3,4-difluoro-2-methoxy-phenoxy)-2-fluoro-3-methyl-benzoyl]amino]pyridine-2-carboxamide(373)

To a solution of4-chloro-6-(3,4-difluoro-2-methoxy-phenoxy)-2-fluoro-3-methyl-benzoicacid (160 mg, 0.462 mmol) and DMF (4 μL, 0.05 mmol) in dichloromethane(3 mL) at 0° C. was added oxalyl chloride (120 μL, 1.42 mmol) dropwise.The mixture was stirred for 2 hours then concentrated in vacuo. Theresidue was dissolved in dichloromethane (3 mL) and added dropwise to amixture of methyl 4-aminopyridine-2-carboxylate (92 mg, 0.61 mmol) andTEA (390 μL, 2.80 mmol) in dichloromethane (3 mL) at 0° C. The resultingmixture was allowed to warm to room temperature and stirred overnight.The mixture was concentrated in vacuo and the resulting residuedissolved in a solution of ammonia in methanol (650 μL of 7 M, 4.6 mmol)and stirred overnight. The mixture was concentrated in vacuo andpurified by reverse phase HPLC (acetonitrile/0.1% ammonium hydroxidegradient), followed by additional reverse phase HPLC purification(0-100% acetonitrile/0.05% trifluoroacetic acid) to provide4-[[4-chloro-6-(3,4-difluoro-2-methoxy-phenoxy)-2-fluoro-3-methyl-benzoyl]amino]pyridine-2-carboxamide(trifluoroacetate salt) (7.9 mg, 3%). ESI-MS m z calc. 465.07, found466.1 (M+1)⁺; 464.1 (M−1)⁻; LC/MS retention time (Method E): 3.24minutes. ¹H NMR (400 MHz, CDCl₃) δ 9.62 (s, 1H), 8.58 (d, J=5.7 Hz, 1H),8.41 (d, J=5.0 Hz, 1H), 8.34 (s, 1H), 8.26 (s, 1H), 7.02-6.89 (m, 2H),6.88 (s, 1H), 6.58 (d, J=1.6 Hz, 1H), 3.91 (d, J=2.0 Hz, 3H), 2.29 (d,J=2.4 Hz, 3H) ppm.

Example 1664-[[3-(cyclopropoxy)-6-(3,4-difluoro-2-methoxy-phenoxy)-2-fluoro-benzoyl]amino]pyridine-2-carboxamide(374)

Step 1: 4-bromo-1-(cyclopropoxy)-2-fluoro-benzene

To a stirring solution of 4-bromo-2-fluoro-phenol (400 mg, 0.0021 mol)in NMP (8 mL) at room temperature were added Cs₂CO₃ (651 mg, 0.0020 mol)followed by bromocyclopropane (373 mg, 0.0030 mol). The mixture washeated at 150° C. for 16 hours. The cooled mixture was diluted withwater and extracted with diethyl ether (2×15 mL). The organic extractswere concentrated in vacuo and purified by silica gel chromatography(100% hexanes) to provide 4-bromo-1-(cyclopropoxy)-2-fluoro-benzene (145mg, 27%) as a colorless liquid. ¹H NMR (400 MHz, CDCl₃) δ 7.26-7.13 (m,3H), 3.8-3.76 (m, 1H), 0.86-0.76 (m, 4H) ppm.

Step 2: 6-bromo-3-(cyclopropoxy)-2-fluoro-benzoic acid

To a stirring solution of 4-bromo-1-(cyclopropoxy)-2-fluoro-benzene (500mg, 0.0020 mol) in THF (5.0 mL) was added LDA (3.7 mL of 2 M, 0.0074mol) at −78° C. The mixture was allowed to warm to room temperature andstirred for 1 hour, then cooled to −78° C. and treated with solid carbondioxide (dry ice, ˜3.0 g). The mixture was stirred for 30 minutes at−78° C. then allowed to warm to room temperature and stirred for 30minutes. The mixture was diluted with water (30 mL) and washed withdiethyl ether (20 mL). The aqueous layer was acidified with 1 M aqueousHCl until pH=2 and extracted with ethyl acetate (3×25 mL). The combinedextracts were dried over Na₂SO₄, filtered and concentrated in vacuo toprovide 6-bromo-3-(cyclopropoxy)-2-fluoro-benzoic acid (350 mg, 62%). ¹HNMR (400 MHz, DMSO-d₆) δ 14.01 (br s, 1H), 7.5-7.39 (m, 2H), 4.02-3.97(m, 1H), 0.85-0.7 (m, 4H) ppm.

Step 3:3-(cyclopropoxy)-6-(3,4-difluoro-2-methoxy-phenoxy)-2-fluoro-benzoicacid

A mixture of 6-bromo-3-(cyclopropoxy)-2-fluoro-benzoic acid (120 mg,0.4363 mmol), 3,4-difluoro-2-methoxy-phenol (70 mg, 0.44 mmol) andCs₂CO₃ (285 mg, 0.875 mmol) in toluene (2 mL) was bubbled with nitrogenfor 5 minutes, then treated with copper (I) iodide (20 mg, 0.11 mmol).The reaction vial was sealed and the mixture heated at 100° C. for 90minutes. The mixture was cooled to room temperature and partitionedbetween ethyl acetate and water. The aqueous layer was acidified to pH=1and the layers separated. The aqueous layer was extracted withadditional ethyl acetate (2×). The combined extracts were washed withbrine, dried over Na₂SO₄, filtered and the concentrated in vacuo.Purification by silica gel chromatography (0-100% ethylacetate/heptane), followed by additional purification by silica gelchromatography (0-50% ethyl acetate/heptane) provided3-(cyclopropoxy)-6-(3,4-difluoro-2-methoxy-phenoxy)-2-fluoro-benzoicacid (124 mg, 80%). ESI-MS m z calc. 354.07, ionization not observed;LC/MS retention time (Method F): 0.63 minutes. ¹H NMR (500 MHz, DMSO-d₆)δ 13.24 (br s, 1H), 7.62 (td, J=8.0, 1.7 Hz, 1H), 7.39 (ddd, J=7.9, 6.2,1.6 Hz, 1H), 7.23 (td, J=8.1, 1.3 Hz, 1H), 6.95 (dd, J=11.3, 8.8 Hz,1H), 3.97 (tt, J=6.2, 3.0 Hz, 1H), 3.87 (s, 3H), 0.88-0.76 (m, 2H),0.75-0.66 (m, 2H) ppm.

Step 4: methyl4-[[3-(cyclopropoxy)-6-(3,4-difluoro-2-methoxy-phenoxy)-2-fluoro-benzoyl]amino]pyridine-2-carboxylate

A solution of3-(cyclopropoxy)-6-(3,4-difluoro-2-methoxy-phenoxy)-2-fluoro-benzoicacid (275 mg, 0.776 mmol) and DMF (5 μL) in dichloromethane (2 mL) at 0°C. was treated dropwise with oxalyl chloride (150 μL, 1.72 mmol) andstirred for 1 hour. The mixture was concentrated in vacuo, then dilutedand evaporated twice with dichloromethane. The residue was dissolved indichloromethane (2 mL) and added to a mixture of methyl4-aminopyridine-2-carboxylate (120 mg, 0.789 mmol) and TEA (450 μL, 3.23mmol) in dichloromethane at 0° C. The mixture was allowed to warm toroom temperature over 18 hours, and then diluted with water (1 mL) andthe phases separated. The organic phase was concentrated and the residuepurified by silica gel chromatography (0-100% ethyl acetate/heptane) toprovide methyl4-[[3-(cyclopropoxy)-6-(3,4-difluoro-2-methoxy-phenoxy)-2-fluoro-benzoyl]amino]pyridine-2-carboxylate(124 mg, 33%). ESI-MS m z calc. 488.12, found 489.0 (M+1)⁺; 487.0(M−1)⁻; LC/MS retention time (Method F): 0.89 minutes. ¹H NMR (500 MHz,DMSO-d₆) δ 11.36 (s, 1H), 8.61 (t, J=5.6 Hz, 1H), 8.36 (d, J=2.0 Hz,1H), 7.83-7.76 (m, 1H), 7.48 (t, J=9.3 Hz, 1H), 7.17 (q, J=9.4 Hz, 1H),6.93-6.85 (m, 1H), 6.77 (dd, J=9.1, 1.6 Hz, 1H), 4.02-3.96 (m, 1H), 3.87(s, 3H), 3.82 (d, J=0.8 Hz, 3H), 0.88-0.69 (m, 4H) ppm.

Step 5:4-[[3-(cyclopropoxy)-6-(3,4-difluoro-2-methoxy-phenoxy)-2-fluoro-benzoyl]amino]pyridine-2-carboxamide(374)

Methyl4-[[3-(cyclopropoxy)-6-(3,4-difluoro-2-methoxy-phenoxy)-2-fluoro-benzoyl]amino]pyridine-2-carboxylate(124 mg, 0.254 mmol) was dissolved in a solution of ammonia in methanol(1 mL of 7 M, 7 mmol) and stirred overnight. The mixture wasconcentrated in vacuo and purified by reverse phase HPLC (47-95%acetonitrile/0.1% ammonium hydroxide) to provide4-[[3-(cyclopropoxy)-6-(3,4-difluoro-2-methoxy-phenoxy)-2-fluoro-benzoyl]amino]pyridine-2-carboxamide(15.2 mg, 13%) as a white solid. ESI-MS m z calc. 473.12, found 474.9(M+1)⁺; 472.0 (M−1)⁻; LC/MS retention time (Method E): 2.97 minutes. ¹HNMR (500 MHz, DMSO-d₆) δ 11.30 (s, 1H), 8.52 (d, J=5.5 Hz, 1H), 8.30 (d,J=2.2 Hz, 1H), 8.07 (d, J=2.8 Hz, 1H), 7.79 (dd, J=5.5, 2.2 Hz, 1H),7.63 (d, J=2.9 Hz, 1H), 7.47 (t, J=9.3 Hz, 1H), 7.23-7.13 (m, 1H), 6.90(ddd, J=9.4, 5.0, 2.2 Hz, 1H), 6.76 (dd, J=9.2, 1.7 Hz, 1H), 3.99 (tt,J=5.9, 2.9 Hz, 1H), 3.83 (d, J=0.8 Hz, 3H), 0.84-0.77 (m, 2H), 0.77-0.68(m, 2H) ppm. ¹⁹F NMR (471 MHz, DMSO-d₆) δ −135.78, −140.97 (d, J=20.9Hz), −152.88 (d, J=21.5 Hz) ppm.

Example 167N-(2-carbamoyl-4-pyridyl)-5-(3,4-difluoro-2-methoxy-phenoxy)-3-methyl-2-(trifluoromethyl)pyridine-4-carboxamide(375)

Step 1: 5-fluoro-3-methyl-2-(trifluoromethyl)pyridine

2-Bromo-5-fluoro-3-methyl-pyridine (7.0 g, 37 mmol) was dissolved in dryNMP (100 mL) under a nitrogen atmosphere. Copper(I) iodide (9.1 g, 48mmol) was added followed by methyl 2,2-difluoro-2-fluorosulfonyl-acetate(17.7 g, 11.7 mL, 92.1 mmol). The mixture was heated at 84° C. overnightwith an attached condenser. The mixture was cooled to room temperatureand the product was isolated by distillation (8.5 mbar, bath temperature95° C.) as a light yellow oil. The oil was diluted in diethyl ether andwashed with saturated aqueous NaHCO₃, dried over MgSO₄ and concentratedin vacuo to afford 5-fluoro-3-methyl-2-(trifluoromethyl)pyridine (6.11g, 93%) as a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 8.36 (d, J=2.6 Hz,1H), 7.38 (dd, J=8.6, 2.7 Hz, 1H), 2.53 (d, J=1.9 Hz, 3H) ppm.

Step 2: 5-fluoro-3-methyl-2-(trifluoromethyl)pyridine-4-carboxylic acid

A solution of diisopropylamine (14.5 mL, 104 mmol) in THF (85 mL) wascooled to −20° C. A solution of n-butyllithium (38 mL of 2.5 M inhexanes, 95 mmol) was added at a rate to maintain internal temperaturebelow −15° C. After the addition was complete, the cooling bath wasremoved and the mixture was allowed to warm to 0° C., and then cooledback to −74° C. A solution of5-fluoro-3-methyl-2-(trifluoromethyl)pyridine (12.83 g, 71.63 mmol) inTHF (40 mL) was added over 30 minutes while maintaining the internaltemperature below −70° C. After the addition was complete, the mixturewas stirred for 30 minutes at −78° C. then poured into a beakercontaining excess solid carbon dioxide (dry ice) in anhydrous THF. Themixture was allowed to warm to room temperature and stirred until nomore effervescence was observed. The mixture was basified with 2 Maqueous NaOH and diluted with water and ethyl acetate. The aqueous phasewas separated and washed with additional ethyl acetate. The aqueousphase was then acidified with 6 M aqueous HCl (to pH=0) and extractedwith ethyl acetate (2×). The combined organic extracts were dried overMgSO₄, filtered and concentrated in vacuo to provide5-fluoro-3-methyl-2-(trifluoromethyl)pyridine-4-carboxylic acid (11.14g, 70% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 14.74 (br s, 1H), 8.78 (s,1H), 2.53-2.48 (m, 3H) ppm.

Step 3: methyl4-[[5-fluoro-3-methyl-2-(trifluoromethyl)pyridine-4-carbonyl]amino]pyridine-2-carboxylate

A solution of 5-fluoro-3-methyl-2-(trifluoromethyl)pyridine-4-carboxylicacid (500 mg, 2.24 mmol) and DMF (5 μL) in 2-MeTHF (2 mL) at 0° C. wastreated dropwise with oxalyl chloride (350 μL, 4.01 mmol) over 10minutes, allowing the bubbles to subside between additions. The mixturewas stirred at 0° C. for 30 minutes. The mixture was concentrated invacuo, then diluted and evaporated twice with dichloromethane. Theresidue was dissolved in 2-MeTHF (2 mL) and added dropwise to a solutionof methyl 4-aminopyridine-2-carboxylate (320 mg, 2.10 mmol) and TEA (600μL, 4.31 mmol) in 2-MeTHF (10 mL) at 0° C. The mixture was allowed towarm to room temperature over 1 hour. The mixture was diluted with water(5 mL) the layers separated. The aqueous layer was extracted with ethylacetate (2×5 mL), and the combined organics dried over Na₂SO₄, filteredand concentrated in vacuo. Purification by silica gel chromatography(0-100% ethyl acetate/heptane) provided methyl4-[[5-fluoro-3-methyl-2-(trifluoromethyl)pyridine-4-carbonyl]amino]pyridine-2-carboxylate(312 mg, 39%) as an off-white solid. ESI-MS m z calc. 357.07, found358.0 (M+1)⁺; 356.0 (M−1)⁻; LC/MS retention time (Method F): 0.72minutes. ¹H NMR (500 MHz, DMSO-d₆) δ 11.56 (s, 1H), 8.82 (s, 1H), 8.66(s, 1H), 8.37 (s, 1H), 7.81 (s, 1H), 3.89 (s, 3H), 2.47 (d, J=1.9 Hz,3H) ppm.

Step 4:N-(2-carbamoyl-4-pyridyl)-5-fluoro-3-methyl-2-(trifluoromethyl)pyridine-4-carboxamide

Methyl4-[[5-fluoro-3-methyl-2-(trifluoromethyl)pyridine-4-carbonyl]amino]pyridine-2-carboxylate(150 mg, 0.420 mmol) was dissolved in methanol (1 mL) and treated with asolution of ammonia in methanol (2 mL of 7 M, 14 mmol). The mixture wasstirred for approximately 72 hours, then concentrated in vacuo andpurified by reverse phase HPLC (acetonitrile/0.1% ammonium hydroxidegradient) to provideN-(2-carbamoyl-4-pyridyl)-5-fluoro-3-methyl-2-(trifluoromethyl)pyridine-4-carboxamide(43 mg, 30%) as a white solid. ESI-MS m z calc. 342.07, found 343.0(M+1)⁺; 341.0 (M−1)⁻; LC/MS retention time (Method F): 0.67 minutes. ¹HNMR (500 MHz, DMSO-d₆) δ 11.50 (s, 1H), 8.82 (s, 1H), 8.59 (d, J=5.5 Hz,1H), 8.32 (d, J=2.2 Hz, 1H), 8.11 (s, 1H), 7.80 (s, 1H), 7.67 (s, 1H),2.47 (q, J=1.9 Hz, 3H) ppm. ¹⁹F NMR (471 MHz, DMSO-d₆) δ −62.35, −62.95ppm.

Step 5:N-(2-carbamoyl-4-pyridyl)-5-(3,4-difluoro-2-methoxy-phenoxy)-3-methyl-2-(trifluoromethyl)pyridine-4-carboxamide(375)

N-(2-carbamoyl-4-pyridyl)-5-fluoro-3-methyl-2-(trifluoromethyl)pyridine-4-carboxamide(45 mg, 0.13 mmol), 3,4-difluoro-2-methoxy-phenol (20 mg, 0.13 mmol) andCs₂CO₃ (100 mg, 0.307 mmol) were combined in acetonitrile (2 mL) andheated to 90° C. overnight. The cooled mixture was diluted with water todissolve the solids and purified directly by reverse phase HPLC (38-53%acetonitrile/0.1% ammonium hydroxide) to provideN-(2-carbamoyl-4-pyridyl)-5-(3,4-difluoro-2-methoxy-phenoxy)-3-methyl-2-(trifluoromethyl)pyridine-4-carboxamide(17.8 mg, 28%) as a white solid. ESI-MS m z calc. 482.10, found 483.0(M+1)⁺; 481.0 (M−1)⁻; LC/MS retention time (Method E): 2.92 minutes. HNMR (500 MHz, DMSO-d₆) δ 11.42 (s, 1H), 8.49 (d, J=5.3 Hz, 1H), 8.27 (s,1H), 8.14 (s, 1H), 8.06 (d, J=3.0 Hz, 1H), 7.74 (s, 1H), 7.60 (s, 1H),7.29-7.18 (m, 1H), 7.11 (ddd, J=9.3, 5.0, 2.1 Hz, 1H), 3.85 (d, J=1.1Hz, 3H), 2.45 (d, J=2.0 Hz, 3H) ppm. ¹⁹F NMR (471 MHz, DMSO-d₆) δ−62.61, −138.96, −152.18 ppm.

Example 1684-[[6-(3,4-difluoro-2-methoxy-phenoxy)-2-fluoro-3-methoxy-4-(trifluoromethyl)benzoyl]amino]-5-methyl-pyridine-2-carboxamide(376)

Step 1: 6-bromo-2-fluoro-3-methoxy-4-(trifluoromethyl)benzoic acid

A solution of 2-fluoro-3-methoxy-4-(trifluoromethyl)benzoic acid (10 g,42 mmol, see Example 94, Step 2) in trifluoroacetic acid (20 mL) andsulfuric acid (5 mL) was treated with N-bromosuccinimide (11.2 g, 62.9mmol) in one portion and the mixture stirred at room temperature for 2.5hours. The resulting thick slurry was diluted with dichloromethane (20mL) and treated with water (20 mL, exotherm observed). The phases wereseparated and the aqueous layer extracted with additionaldichloromethane (4×20 mL). The organic extracts were combined, dilutedwith heptane (50 mL) and cooled in an ice water bath. The resultingwhite crystals were collected by filtration to provide 11.94 g of solid.The solid was slurried in ice-cold dichloromethane (50 mL) and filteredto provide 5.15 g of6-bromo-2-fluoro-3-methoxy-4-(trifluoromethyl)benzoic acid. Anadditional crop of product (1.9 g) was obtained by slurring andfiltering the concentrated mother liquors in ice-cold heptane. Themother liquor was concentrated in vacuo and purified by silica gelchromatography. (0-100% ethyl acetate/heptane) to provide 7 g ofproduct. All the product solids were then combined in ethyl acetate andconcentrated in vacuo to provide6-bromo-2-fluoro-3-methoxy-4-(trifluoromethyl)benzoic acid (12.77 g,96%). ¹H NMR (400 MHz, CDCl₃) δ 7.65 (dd, J=1.9, 0.7 Hz, 1H), 5.32 (s,1H), 4.07 (d, J=2.3 Hz, 3H) ppm. ESI-MS m z calc. 315.94, no ionizationdetected; LC/MS retention time (Method F): 0.41 minutes.

Step 2:6-(3,4-difluoro-2-methoxy-phenoxy)-2-fluoro-3-methoxy-4-(trifluoromethyl)benzoicacid

A solution of 6-bromo-2-fluoro-3-methoxy-4-(trifluoromethyl)benzoic acid(2.000 g, 6.309 mmol), 3,4-difluoro-2-methoxy-phenol (1.002 g, 6.258mmol) and Cs₂CO₃ (2.275 g, 6.982 mmol) in toluene (12 mL) was flushedwith nitrogen for 10 minutes. Copper (I) iodide (480 mg, 2.52 mmol) wasadded and the mixture heated at 100° C. under nitrogen for 20 hours. Thecooled mixture was partitioned between ethyl acetate (100 mL) and water(100 mL), and the aqueous layer washed with additional ethyl acetate(2×100 mL). The aqueous layer was acidified to pH=3 with 2 M aqueous HCland extracted with ethyl acetate (3×100 mL). The combined organic layerswere dried over MgSO₄, filtered and concentrated in vacuo. Purificationby silica gel chromatography (0-30% ethyl acetate/heptane gradient,followed by elution with 3:1 ethyl acetate/ethanol) provided6-(3,4-difluoro-2-methoxy-phenoxy)-2-fluoro-3-methoxy-4-(trifluoromethyl)benzoicacid (333 mg, 13%). ESI-MS m z calc. 396.04, found 395.1 (M−1)⁻; LC/MSretention time (Method F): 0.6 minutes. ¹H NMR (500 MHz, DMSO-d₆) δ 7.20(q, J=9.7 Hz, 1H), 6.98-6.93 (m, 1H), 6.91 (s, 1H), 3.94 (d, J=1.4 Hz,3H), 3.88 (d, J=0.9 Hz, 3H) ppm.

Step 3: methyl4-[[6-(3,4-difluoro-2-methoxy-phenoxy)-2-fluoro-3-methoxy-4-(trifluoromethyl)benzoyl]amino]-5-methyl-pyridine-2-carboxylate

A solution of6-(3,4-difluoro-2-methoxy-phenoxy)-2-fluoro-3-methoxy-4-(trifluoromethyl)benzoicacid (125 mg, 0.316 mmol) in 2-MeTHF (5 mL) and DMF (3 μL, 0.04 mmol)was treated with oxalyl chloride (55 μL, 0.63 mmol). The mixture warmedto room temperature and stirred for 30 minutes, then concentrated invacuo. The residue was dissolved in 2-MeTHF (3 mL) and NMP (1 mL), thenadded to a solution of methyl 4-amino-5-methyl-pyridine-2-carboxylate(57.1 mg, 0.344 mmol, Preparation 1) and TEA (200 μL, 1.44 mmol) in2-MeTHF (3 mL) at 0° C. The mixture was warmed to room temperature andstirred for 90 minutes. The mixture was diluted with ethyl acetate (30mL) and washed with water (4×30 mL). The organic layer was dried overMgSO₄, filtered and concentrated in vacuo. Purification by silica gelchromatography (0-70% ethyl acetate/heptane) provided methyl4-[[6-(3,4-difluoro-2-methoxy-phenoxy)-2-fluoro-3-methoxy-4-(trifluoromethyl)benzoyl]amino]-5-methyl-pyridine-2-carboxylate(63 mg, 37%). ESI-MS m z calc. 544.11, found 544.9 (M+1)⁺; 543.0 (M−1)⁻;LC/MS retention time (Method F): 0.95 minutes.

Step 4:4-[[6-(3,4-difluoro-2-methoxy-phenoxy)-2-fluoro-3-methoxy-4-(trifluoromethyl)benzoyl]amino]-5-methyl-pyridine-2-carboxamide(376)

Methyl4-[[6-(3,4-difluoro-2-methoxy-phenoxy)-2-fluoro-3-methoxy-4-(trifluoromethyl)benzoyl]amino]-5-methyl-pyridine-2-carboxylate(63 mg, 0.12 mmol) was dissolved in a solution of ammonia in methanol (1mL of 7 M, 7 mmol) and stirred at room temperature for 48 hours. Themixture was concentrated in vacuo and purified by reverse phase HPLC(47-95% acetonitrile/0.1% ammonium hydroxide) to provide4-[[6-(3,4-difluoro-2-methoxy-phenoxy)-2-fluoro-3-methoxy-4-(trifluoromethyl)benzoyl]amino]-5-methyl-pyridine-2-carboxamide(29 mg, 47%). ESI-MS m z calc. 529.10, found 529.8 (M+1)⁺; 528.0 (M−1)⁻;LC/MS retention time (Method E): 3.21 minutes. ¹H NMR (500 MHz, DMSO-d₆)δ 10.59 (s, 1H), 8.48 (s, 1H), 8.43 (s, 1H), 8.05 (s, 1H), 7.60 (s, 1H),7.23 (q, J=9.3 Hz, 1H), 7.09-7.01 (m, 1H), 6.96 (s, 1H), 3.99 (d, J=1.3Hz, 3H), 3.88 (d, J=1.0 Hz, 3H), 2.29 (s, 3H) ppm.

Example 1695-[[6-(3,4-difluoro-2-methoxy-phenoxy)-2-fluoro-3-methoxy-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(377)

This compound was made in an analogous fashion to the synthesis ofcompound 376 in Example 168, except employing5-aminopyridine-2-carboxamide for the amide formation step. The yield of5-[[6-(3,4-difluoro-2-methoxy-phenoxy)-2-fluoro-3-methoxy-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamidewas 45 mg (24%). ESI-MS m z calc. 515.09, found 516.0 (M+1)⁺; 514.0(M−1)+; LC/MS retention time (Method E): 3.14 minutes. ¹H NMR (500 MHz,DMSO-d₆) δ 11.38 (s, 1H), 8.82 (d, J=2.4 Hz, 1H), 8.26 (dd, J=8.6, 2.5Hz, 1H), 8.06 (d, J=8.5 Hz, 1H), 8.01 (s, 1H), 7.64-7.48 (m, 1H), 7.21(td, J=9.7, 8.5 Hz, 1H), 7.04 (dt, J=4.5, 2.2 Hz, 1H), 6.98 (d, J=1.5Hz, 1H), 3.98 (d, J=1.2 Hz, 3H), 3.84 (d, J=1.0 Hz, 3H) ppm.

Example 1704-[[6-(3,4-difluoro-2-methoxy-phenoxy)-4-methoxy-2-(methylamino)-3-(trifluoromethyl)benzoyl]amino]-N-methyl-pyridine-2-carboxamide(378)

And Example 1714-[[6-(3,4-difluoro-2-methoxy-phenoxy)-2-fluoro-4-methoxy-3-(trifluoromethyl)benzoyl]amino]-N-methyl-pyridine-2-carboxamide(379)

Step 1:6-(3,4-difluoro-2-methoxy-phenoxy)-2-fluoro-4-methoxy-3-(trifluoromethyl)benzoicacid

A mixture of 6-bromo-2-fluoro-4-methoxy-3-(trifluoromethyl)benzoic acid(2.15 g, 6.78 mmol, see US 2019/0016671, Example 129, Step 3, which isincorporated by reference), 3,4-difluoro-2-methoxy-phenol (1.0 g, 6.3mmol) and Cs₂CO₃ (2.3 g, 7.1 mmol) in toluene (10 mL) was bubbled withnitrogen for 10 minutes, then copper (I) iodide (456 mg, 2.39 mmol) wasadded. The mixture was heated at 100° C. under nitrogen with vigorousstirring for 1.5 hours. The cooled mixture was acidified with 1 Maqueous HCl (15 mL), filtered and the aqueous layer extracted with ethylacetate (3×50 mL). The organic layer was washed with brine, dried overMgSO₄, filtered and concentrated in vacuo. Purification by silica gelchromatography (0-100% ethyl acetate/heptane) provided6-(3,4-difluoro-2-methoxy-phenoxy)-2-fluoro-4-methoxy-3-(trifluoromethyl)benzoicacid (2.105 g, 78%) as an off-white solid. ESI-MS m z calc. 396.04,found 396.8 (M+1)⁺; 395.0 (M−1)⁻; LC/MS retention time (Method F): 0.55minutes. ¹H NMR (500 MHz, DMSO-d₆) δ 13.71 (s, 1H), 7.28-7.22 (m, 1H),7.08 (ddd, J=9.3, 5.1, 2.2 Hz, 1H), 6.41 (s, 1H), 3.89 (d, J=0.9 Hz,3H), 3.78 (s, 3H) ppm. ¹⁹F NMR (471 MHz, DMSO-d₆) δ −54.63 (d, J=29.9Hz), −114.37 (q, J=30.3 Hz), −139.34 (d, J=22.0 Hz), −152.12 (d, J=22.0Hz) ppm.

Step 2: methyl4-[[6-(3,4-difluoro-2-methoxy-phenoxy)-2-fluoro-4-methoxy-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxylate

To a solution of6-(3,4-difluoro-2-methoxy-phenoxy)-2-fluoro-4-methoxy-3-(trifluoromethyl)benzoicacid (500 mg, 1.26 mmol) and DMF (10 μL, 0.13 mmol) in dichloromethane(6 mL) at 0° C. was added oxalyl chloride (250 μL, 2.87 mmol). Themixture was allowed to warm to room temperature over 30 minutes and wasthen concentrated in vacuo. The residue was dissolved in dichloromethane(3 mL) and added to a solution of methyl 4-aminopyridine-2-carboxylate(240 mg, 1.58 mmol) and TEA (250 μL, 1.79 mmol) in dichloromethane (3mL) at 0° C. The resulting mixture was stirred and warmed to ambienttemperature over 2 hours. The mixture was diluted with aqueous NH₄Clsolution and extracted with dichloromethane (2×5 mL). The combinedorganic extracts were dried over MgSO₄, filtered and concentrated invacuo. Purification by silica gel chromatography (0-100% ethylacetate/hexane) provided methyl4-[[6-(3,4-difluoro-2-methoxy-phenoxy)-2-fluoro-4-methoxy-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxylate(200 mg, 30%). ESI-MS m z calc. 530.09, found 531.0 (M+1)⁺; 529.1 (M−1);LC/MS retention time (Method E): 3.21 minutes.

Step 3:4-[[6-(3,4-difluoro-2-methoxy-phenoxy)-4-methoxy-2-(methylamino)-3-(trifluoromethyl)benzoyl]amino]-N-methyl-pyridine-2-carboxamide(378) And4-[[6-(3,4-difluoro-2-methoxy-phenoxy)-2-fluoro-4-methoxy-3-(trifluoromethyl)benzoyl]amino]-N-methyl-pyridine-2-carboxamide(379)

Methyl4-[[6-(3,4-difluoro-2-methoxy-phenoxy)-2-fluoro-4-methoxy-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxylate(100 mg, 0.189 mmol) was dissolved in a solution of MeNH₂ in methanol(20 mL of 2 M, 40 mmol) and stirred for 60 hours at room temperature.The mixture was concentrated in vacuo and the residue purified byreverse phase HPLC (0-100% acetonitrile/0.05% trifluoroacetic acid) toafford the following two compounds:

4-[[6-(3,4-difluoro-2-methoxy-phenoxy)-4-methoxy-2-(methylamino)-3-(trifluoromethyl)benzoyl]amino]-N-methyl-pyridine-2-carboxamide(378) (16.3 mg, 16%). ESI-MS m/z calc. 540.14, found 541.1 (M+1)⁺; 539.2(M−1)⁻; LC/MS retention time (Method E): 3.12 minutes. ¹H NMR (500 MHz,DMSO-d₆) δ 11.09 (s, 1H), 8.71 (d, J=4.9 Hz, 1H), 8.49 (d, J=5.5 Hz,1H), 8.30 (d, J=2.5 Hz, 1H), 7.84 (dd, J=5.4, 2.1 Hz, 1H), 7.27-7.12 (m,1H), 7.06-6.89 (m, 1H), 5.85 (s, 1H), 5.60 (s, 1H), 3.81 (s, 3H), 3.65(s, 3H), 2.84 (s, 3H), 2.81 (d, J=4.9 Hz, 3H) ppm; and4-[[6-(3,4-difluoro-2-methoxy-phenoxy)-2-fluoro-4-methoxy-3-(trifluoromethyl)benzoyl]amino]-N-methyl-pyridine-2-carboxamide(379) (2.7 mg, 3%). ESI-MS m/z calc. 529.11, found 530.1 (M+1)⁺; 528.2(M−1)⁻; LC/MS retention time (Method E): 3.18 minutes. ¹H NMR (400 MHz,DMSO-d₆) δ 11.34 (s, 1H), 8.82-8.73 (m, 1H), 8.55 (d, J=5.5 Hz, 1H),8.27 (d, J=2.2 Hz, 1H), 7.84 (dd, J=5.8, 2.2 Hz, 1H), 7.25 (q, J=9.3 Hz,1H), 7.20-7.08 (m, 1H), 6.44 (s, 1H), 3.86 (s, 3H), 3.81 (s, 3H), 2.82(d, J=4.7 Hz, 3H) ppm.

Example 1725-[[6-(3,4-difluoro-2-methoxy-phenoxy)-2-fluoro-4-methoxy-3-(trifluoromethyl)benzoyl]amino]pyrimidine-2-carboxamide(380)

This compound was made in an analogous fashion to Example 171, exceptemploying methyl 5-aminopyrimidine-2-carboxylate for the amide formationstep. The yield of methyl5-[[6-(3,4-difluoro-2-methoxy-phenoxy)-2-fluoro-4-methoxy-3-(trifluoromethyl)benzoyl]amino]pyrimidine-2-carboxylatewas 195 mg (36%). ESI-MS m z calc. 531.09, found 532.0 (M+1)⁺; 530.0(M−1)+; LC/MS retention time (Method F): 0.9 minutes. ¹H NMR (500 MHz,DMSO-d₆) δ 11.51 (s, 1H), 9.20 (s, 2H), 7.24 (q, J=9.3 Hz, 1H), 7.12 (d,J=8.4 Hz, 1H), 6.48 (d, J=20.6 Hz, 1H), 3.89 (s, 3H), 3.86 (d, J=1.3 Hz,3H), 3.81 (s, 3H) ppm.

Analogous treatment with methanolic ammonia provided5-[[6-(3,4-difluoro-2-methoxy-phenoxy)-2-fluoro-4-methoxy-3-(trifluoromethyl)benzoyl]amino]pyrimidine-2-carboxamide(38 mg, 19%). ESI-MS m/z calc. 516.09, found 517.1 (M+1)⁺; 515.1 (M−1)⁻;LC/MS retention time (Method E): 2.84 minutes. ¹H NMR (500 MHz, DMSO-d₆)δ 11.41 (s, 1H), 9.15 (s, 2H), 8.11 (s, 1H), 7.71 (s, 1H), 7.29-7.19 (m,1H), 7.12 (ddd, J=9.4, 5.1, 2.1 Hz, 1H), 6.47 (s, 1H), 3.87 (d, J=1.1Hz, 3H), 3.81 (s, 3H) ppm.

Example 1735-[[6-(3,4-difluoro-2-methoxy-phenoxy)-2-fluoro-4-methoxy-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(381)

This compound was made in an analogous fashion to Example 171, exceptemploying 5-aminopyridine-2-carboxamide for the amide formation step.The yield of5-[[6-(3,4-difluoro-2-methoxy-phenoxy)-2-fluoro-4-methoxy-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamideafter purification by silica gel chromatography (0-40% ethylacetate/hexane) was 47 mg (10%). ESI-MS m z calc. 515.09, found 516.0(M+1)⁺; 514.1 (M−1)+; LC/MS retention time (Method E): 3.03 minutes. ¹HNMR (500 MHz, DMSO-d₆) δ 11.24 (s, 1H), 8.82 (s, 1H), 8.27 (dd, J=8.6,2.5 Hz, 1H), 8.04 (d, J=8.4 Hz, 2H), 7.58 (s, 1H), 7.25 (q, J=9.4 Hz,1H), 7.16-7.08 (m, 1H), 6.45 (s, 1H), 3.87 (d, J=1.1 Hz, 3H), 3.81 (s,3H) ppm.

Example 1744-(6-(2-chloro-4-fluorophenoxy)-2-fluoro-3-methoxy-4-(trifluoromethyl)benzamido)-5-methylpicolinamide(382)

Step 1:6-(2-chloro-4-fluoro-phenoxy)-2-fluoro-3-methoxy-4-(trifluoromethyl)benzoicacid

A mixture of 6-bromo-2-fluoro-3-methoxy-4-(trifluoromethyl)benzoic acid(220 mg, 0.694 mmol), 2-chloro-4-fluoro-phenol (80 μL, 0.74 mmol) andCs₂CO₃ (340 mg, 1.044 mmol) in toluene (1 mL) was bubbled with nitrogenfor 10 minutes, then copper (I) iodide (50 mg, 0.2625 mmol) was added.The mixture was heated at 125° C. with vigorous stirring for 4 hoursunder nitrogen. The mixture was cooled to room temperature and acidifiedwith 1 M aqueous HCl (15 mL), filtered and extracted with ethyl acetate(3×50 mL). The combined extracts were washed with brine (10 mL), driedover MgSO₄, filtered and concentrated in vacuo. The residue was purifiedby silica gel chromatography (0-100% ethyl acetate/heptane) to provide6-(2-chloro-4-fluoro-phenoxy)-2-fluoro-3-methoxy-4-(trifluoromethyl)benzoicacid (120 mg, 43%). ESI-MS m z calc. 382.00, found 380.8 (M−1)⁻; LC/MSretention time (Method F): 0.74 minutes.

Step 2:4-(6-(2-chloro-4-fluorophenoxy)-2-fluoro-3-methoxy-4-(trifluoromethyl)benzamido)-5-methylpicolinamide(382)

Using6-(2-chloro-4-fluoro-phenoxy)-2-fluoro-3-methoxy-4-(trifluoromethyl)benzoicacid above, this compound was made in an analogous fashion to steps 3and 4 of Example 168. ESI-MS m z calc. 515.07, found 515.8 (M+1)⁺; 513.9(M−1)⁻; LC/MS retention time (Method E): 3.8 minutes.

Example 2014-[(Z)-[(tert-Butylamino)-phenylsulfanyl-methylene]amino]pyridine-2-carboxamide

A flask equipped with a reflux condenser was charged with4-aminopyridine-2-carboxamide (1.12 g, 8.17 mmol),benzenesulfonylsulfanylbenzene (1.85 g, 7.39 mmol),2-isocyano-2-methyl-propane (3.0 mL, 27 mmol), copper (I) iodide (60 mg,0.32 mmol) and molecular sieves (2.2 g) in 2-methyltetrahydrofuran (10mL), and the mixture was heated at 75° C. for 24 hours. The reactionmixture was filtered through Celite and the cake was rinsed with ethylacetate. The filtrate was concentrated and dried under vacuum. Theresidue was purified by silica gel chromatography (ethyl acetate/hexanesgradient) to obtain4-[(Z)-[(tert-butylamino)-phenylsulfanyl-methylene]amino]pyridine-2-carboxamide(1.25 g, 51%). ESI-MS m/z calc. 328.14, found 329.2 (M+1)⁺; retentiontime (Method B): 1.07 minutes. ¹H NMR (400 MHz, DMSO-d6) δ 8.17 (dd,J=5.3, 0.6 Hz, 1H), 7.94 (d, J=3.0 Hz, 1H), 7.49 (s, 1H), 7.28 (dd,J=2.2, 0.6 Hz, 1H), 7.25-7.17 (m, 5H), 6.74 (dd, J=5.3, 2.2 Hz, 1H),6.66 (s, 1H), 1.35 (s, 9H) ppm.

Example 2024-[[4-(cyclohexen-1-yl)-2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(1001)

Step 1: 1-bromo-2-(trideuteriomethoxy)-4-(trifluoromethoxy)benzene

2-Bromo-5-(trifluoromethoxy)phenol (57.5 g, 224 mmol) in DMF (400 mL)was treated with K₂CO₃ (62 g, 450 mmol), stirred for 15 minutes, andcooled in an ice bath, and iodomethane-d3 (Aldrich, >99.5% D, 15.3 mL,246 mmol) was added dropwise. The pale yellow suspension was removedfrom the ice bath and stirred at RT for 16 hours. The suspension waspartitioned between water (2 L) and MTBE (500 mL) and separated. Theorganic phase was washed with 0.5 M NaOH (500 mL) and brine (2×300 mL)and the aqueous phases were back extracted once with MTBE (250 mL). Thecombined organic phases were dried, filtered and evaporated to give1-bromo-2-(trideuteriomethoxy)-4-(trifluoromethoxy)benzene (62.4 g, 97%)as a pale yellow liquid. LC/MS retention time (Method B): 1.84 minutes.¹H NMR (400 MHz, DMSO-d6) δ 7.71 (d, J=8.7 Hz, 1H), 7.14 (d, J=2.6 Hz,1H), 6.92 (ddq, J=8.7, 2.5, 1.3 Hz, 1H) ppm.

Step 2: 2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenol

A 1000-mL 3-neck round-bottom flask was fitted with a mechanicalstirrer, a heating mantle, a water cooled reflux condenser, temperatureprobe/controller and a nitrogen inlet/outlet was charged under anitrogen atmosphere with tetrabutylammonium hydroxide (355 mL of 55%w/w, 730 mmol) and1-bromo-2-(trideuteriomethoxy)-4-(trifluoromethoxy)benzene (50.0 g, 182mmol). With stirring, the solution was degassed with nitrogen for 15minutes. 1,10-Phenanthroline-4,7-diol (3.871 g, 18.24 mmol) was thenadded as a solid in one portion followed by copper (I) oxide (1.305 g,9.120 mmol) added as a solid in one portion. After these additions, thegas dispersion tube was removed and the vessel was fitted with a septum.The resulting mixture was then heated to a pot temperature of 100° C.for 15 hours. After cooling to RT, the reaction mixture was poured intoice cold hydrochloric acid (912 mL of 1 M, 912 mmol). The mixture wasdiluted with ethyl acetate (500 mL) and mixed for several minutes. Thephases were separated and the aqueous phase was extracted with ethylacetate (2×200 mL). The combined organic phases were washed with brine(2×250 mL), dried over Na₂SO₄ (200 g), filtered and concentrated. Theresidue was purified by silica gel chromatography (ethyl acetate/hexanesgradient) to provide 2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenol(33 g, 86%) as a clear pale yellow oil. LC/MS retention time (Method B):1.38 minutes. ¹H NMR (400 MHz, DMSO-d6) δ 9.31 (s, 1H), 6.91 (dd, J=2.8,0.9 Hz, 1H), 6.82 (d, J=8.6 Hz, 1H), 6.79-6.70 (m, 1H) ppm.

Step 3: methyl4-bromo-2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoate

A mixture of Cs₂CO₃ (7.89 g, 24.2 mmol),2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenol (3.54 g, 16.8 mmol)and methyl 4-bromo-2,6-difluoro-benzoate (4.00 g, 15.9 mmol) in DMF (70mL) was stirred at RT for 20 hours. The reaction was diluted with ethylacetate and washed with water (3×) and brine. The organic layer wasdried over anhydrous MgSO₄, filtered and concentrated under reducedpressure. Silica gel chromatography (ethyl acetate/hexanes gradient)provided methyl4-bromo-2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoate(6.09 g, 86%). ESI-MS m/z calc. 440.99, found 443.1 (M+1)⁺; Retentiontime (Method A): 0.82 minutes. ¹H NMR (400 MHz, DMSO-d6) δ 7.47 (dd,J=9.0, 1.7 Hz, 1H), 7.26 (d, J=8.8 Hz, 1H), 7.24 (d, J=2.8 Hz, 1H), 7.00(ddd, J=8.8, 2.7, 1.3 Hz, 1H), 6.73 (t, J=1.5 Hz, 1H), 3.83 (s, 3H) ppm.

Step 4:4-bromo-2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoicacid

Methyl4-bromo-2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoate(6.09 g, 13.8 mmol) was dissolved in methanol (60 mL) and treated withNaOH (40 mL of 1 M, 40 mmol). The reaction was heated to 40° C. andstirred for 2 hours. Additional NaOH (23 mL of 6 M, 138 mmol) was addedand the reaction stirred at 45° C. for 1 hour. The reaction mixture wasacidified with aqueous HCl (210 mL of 1 M, 210 mmol) and extracted withethyl acetate (3×). The combined organic layers were dried overanhydrous MgSO₄, filtered and concentrated in vacuo to provide4-bromo-2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoicacid (5.81 g, 99%) as a glassy oil. ESI-MS m/z calc. 426.98, found 429.0(M+1)⁺; Retention time (Method A): 0.72 minutes. H NMR (400 MHz,DMSO-d6) δ 13.78 (s, 1H), 7.42 (dd, J=8.9, 1.6 Hz, 1H), 7.25-7.20 (m,2H), 7.00 (ddd, J=8.8, 2.7, 1.3 Hz, 1H), 6.67 (t, J=1.4 Hz, 1H) ppm.

Step 5:4-[[4-bromo-2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide

To a solution of4-bromo-2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoicacid (4.0 g, 9.3 mmol), DMF (210 μL, 2.71 mmol) in dichloromethane (48mL) at 0° C. under nitrogen was added oxalyl chloride (7 mL, 80 mmol).The reaction was stirred at 0° C. for 10 minutes and then at RT for 1hour. The mixture was concentrated under reduced pressure and theresidue was dissolved in NMP (5 mL). This solution was added dropwise toa suspension of 4-aminopyridine-2-carboxamide (1.28 g, 9.33 mmol) in DMF(1.5 mL), DIEA (10 mL, 57 mmol) and NMP (10 mL) under nitrogenatmosphere at 0° C. The reaction mixture was allowed to warm to RT andstirred for 16 hours. The mixture was partitioned between water andethyl acetate. The phases were separated and the aqueous layer wasextracted with ethyl acetate. The combined organic layers were washedwith water (2×) and brine. The organic layer was dried over Na₂SO₄,filtered and concentrated. The crude product was purified by silicachromatography (ethyl acetate/hexanes gradient) to provide4-[[4-bromo-2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(1.26 g, 25%). ESI-MS m/z calc. 546.02, found 549.0 (M+1)⁺; Retentiontime (Method B): 1.94 minutes. ¹H NMR (400 MHz, DMSO-d6) δ 11.30 (s,1H), 8.54 (d, J=5.4 Hz, 1H), 8.29 (d, J=2.1 Hz, 1H), 8.16-7.99 (m, 1H),7.82 (dd, J=5.6, 2.2 Hz, 1H), 7.65 (d, J=2.8 Hz, 1H), 7.52 (dd, J=8.6,1.5 Hz, 1H), 7.30 (d, J=8.8 Hz, 1H), 7.20 (d, J=2.7 Hz, 1H), 7.10-6.91(m, 1H), 6.75 (s, 1H) ppm.

Step 6:4-[[4-(cyclohexen-1-yl)-2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(1001)

A solution of4-[[4-bromo-2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(25 mg, 0.046 mmol), cyclohexen-1-ylboronic acid (14 mg, 0.11 mmol),K₂CO₃ (13 mg, 0.094 mmol) and Pd(dppf)Cl₂.DCM (8 mg, 0.01 mmol) indioxane (500 μL) and water (50 μL) was heated at 100° C. for 16 hours.The reaction mixture was filtered and purified by HPLC (10-99% CH₃CN/5mM HCl) to provide4-[[4-(cyclohexen-1-yl)-2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(18 mg, 72%). ESI-MS m/z calc. 548.18, found 549.01 (M+1)⁺; Retentiontime (Method B): 2.07 minutes. ¹H NMR (400 MHz, DMSO-d6) δ 11.24 (s,1H), 8.52 (d, J=5.5 Hz, 1H), 8.29 (d, J=2.2 Hz, 1H), 8.11 (s, 1H),7.86-7.77 (m, 1H), 7.65 (s, 1H), 7.20 (d, J=8.8 Hz, 1H), 7.15 (dd,J=6.8, 4.0 Hz, 2H), 6.97 (d, J=9.3 Hz, 1H), 6.57 (s, 1H), 6.18 (s, 1H),2.23 (s, 2H), 2.14 (s, 2H), 1.66 (d, J=6.2 Hz, 2H), 1.56 (d, J=7.1 Hz,2H) ppm.

The compounds set forth in Table 102 were prepared by methods analogousto the preparation of compound 1001:

TABLE 102 Additional Compounds Prepared by Methods Analogous to Example202 Cmpd No. Compound Name LC/MS NMR (shifts in ppm) 10024-[[4-(3,4-dihydro-2H- ESI-MS m/z pyran-5-yl)-2-fluoro-6- calc. 550.16,[2- found 551.1 (trideuteriomethoxy)-4- (M + 1)+; (trifluoromethoxy)phe-Retention time noxy]benzoyl]amino]pyr- (Method B): idine-2-carboxamide1.19 minutes. 1003 4-[[4-(4,4- ESI-MS m/z ¹H NMR (400 MHz, DMSO-d6) δdifluorocyclohexen-1- calc. 584.16, 11.26 (s, 1H), 8.52 (d, J = 5.5 Hz,yl)-2-fluoro-6-[2- found 585.01 1H), 8.30 (d, J = 2.0 Hz, 1H), 8.11(trideuteriomethoxy)-4- (M + 1)+; (s, 1H), 7.85-7.77 (m, 1H), 7.66 (s,(trifluoromethoxy)phe- Retention time 1H), 7.23 (dd, J = 11.6, 9.6 Hz,2H), noxy]benzoyl]amino]pyr- (Method B): 7.16 (d, J = 2.6 Hz, 1H),7.01-6.90 idine-2-carboxamide 1.94 minutes. (m, 1H), 6.65 (s, 1H), 6.04(s, 1H), 2.72 (t, J = 15.0 Hz, 2H), ~2.5 (2H, obscured by DMSO peak),2.14 (tt, J = 14.0, 6.6 Hz, 2H). 1004 4-[[4-(2,5- ESI-MS m/zdihydrofuran-3-yl)-2- calc. 536.14, fluoro-6-[2- found 537.3(trideuteriomethoxy)-4- (M + 1)+; (trifluoromethoxy)phe- Retention timenoxy]benzoyl]amino]pyr- (Method B): idine-2-carboxamide 1.58 minutes.1005 4-[[4-(3,6-dihydro-2H- ESI-MS m/z pyran-4-yl)-2-fluoro-6- calc.550.16, [2- found 551.3 (trideuteriomethoxy)-4- (M + 1)+;(trifluoromethoxy)phe- Retention time noxy]benzoyl]amino]pyr- (MethodB): idine-2-carboxamide 1.6 minutes. 1006 4-[[4-(2- ESI-MS m/z ¹H NMR(400 MHz, DMSO-d6) δ carbamoylphenyl)-2- calc. 587.15, 11.43 (s, 1H),8.54 (d, J = 5.5 Hz, fluoro-6-[2- found 588.3 1H), 8.34 (d, J = 2.1 Hz,1H), 8.12 (trideuteriomethoxy)-4- (M + 1)+; (s, 1H), 7.86 (dd, J = 5.6,2.2 Hz, (trifluoromethoxy)phe- Retention time 1H), 7.78 (s, 1H), 7.67(s, 1H), 7.53- noxy]benzoyl]amino]pyr- (Method B): 7.39 (m, 3H), 7.32(d, J = 8.3 Hz, idine-2-carboxamide 1.74 minutes. 2H), 7.27 (d, J = 8.8Hz, 1H), 7.18- 7.10 (m, 2H), 6.99 (d, J = 8.8 Hz, 1H), 6.60 (s, 1H).1007 4-[[2-fluoro-4-(4- ESI-MS m/z ¹H NMR (400 MHz, DMSO-d6) δmethoxyphenyl)-6-[2- calc. 574.16, 11.28 (s, 1H), 8.53 (d, J = 5.5 Hz,(trideuteriomethoxy)-4- found 575.2 1H), 8.31 (s, 1H), 8.11 (s, 1H),7.85- (trifluoromethoxy)phe- (M + 1)+; 7.77 (m, 1H), 7.66 (s, 1H), 7.55(t, noxy]benzoyl]amino]pyr- Retention time J = 8.0 Hz, 3H), 7.46-7.37(m, idine-2-carboxamide (Method B): 1H), 7.27 (d, J = 8.8 Hz, 1H), 7.171.82 minutes. (d, J = 2.8 Hz, 1H), 7.04-6.95 (m, 2H), 6.80 (s, 1H), 3.78(d, J = 1.8 Hz, 3H). 1008 4-[[4-(2,3- ESI-MS m/z dihydrofuran-4-yl)-2-calc. 536.14, fluoro-6-[2- found 537.3 (trideuteriomethoxy)-4- (M + 1)+;(trifluoromethoxy)phe- Retention time noxy]benzoyl]amino]pyr- (MethodB): idine-2-carboxamide 1.64 minutes. 1009 4-[[2-fluoro-4-(4- ESI-MS m/z¹H NMR (400 MHz, DMSO-d6) δ methoxycyclohexen-1- calc. 578.19, 11.27 (s,1H), 8.53 (d, J = 5.5 Hz, yl)-6-[2- found 579.3 1H), 8.31 (s, 1H), 8.13(s, 1H), 7.87- (trideuteriomethoxy)-4- (M + 1)+; 7.79 (m, 1H), 7.69 (s,1H), 7.27- (trifluoromethoxy)phe- Retention time 7.13 (m, 3H), 7.01-6.91(m, 1H), noxy]benzoyl]amino]pyr- (Method B): 6.58 (s, 1H), 6.07 (s, 1H),3.25 (s, idine-2-carboxamide 1.76 minutes. 3H), ~2.5 (2H, obscured byDMSO), 2.44 (d, 1H), 2.33 (t, J = 15.1 Hz, 1H), 2.09 (d, J = 18.6 Hz,1H), 1.90 (d, J = 12.1 Hz, 1H), 1.65 (dq, J = 13.9, 7.4 Hz, 1H). 10104-[[4-(cyclopenten-1- ESI-MS m/z yl)-2-fluoro-6-[2- calc. 534.16,(trideuteriomethoxy)-4- found 534.96 (trifluoromethoxy)phe- (M + 1)+;noxy]benzoyl]amino]pyr- Retention time idine-2-carboxamide (Method B):2.01 minutes. 1011 4-[[4-(3-cyanophenyl)- ESI-MS m/z ¹H NMR (400 MHz,DMSO-d6) δ 2-fluoro-6-[2- calc. 569.14, 11.34 (s, 1H), 8.54 (d, J = 5.5Hz, (trideuteriomethoxy)-4- found 570.2 1H), 8.31 (d, J = 2.1 Hz, 1H),8.18 (trifluoromethoxy)phe- (M + 1)+; (t, J = 1.8 Hz, 1H), 8.11 (d, J =2.8 noxy]benzoyl]amino]pyr- Retention time Hz, 1H), 7.97 (dt, J = 8.1,1.6 Hz, idine-2-carboxamide (Method B): 1H), 7.89 (dt, J = 7.7, 1.4 Hz,1H), 1.97 minutes. 7.83 (dd, J = 5.5, 2.2 Hz, 1H), 7.72- 7.63 (m, 2H),7.62 (dd, J = 10.2, 1.5 Hz, 1H), 7.25 (d, J = 8.8 Hz, 1H), 7.15 (d, J =2.8 Hz, 1H), 7.04 (d, J = 1.5 Hz, 1H), 6.96 (ddd, J = 8.9, 2.9, 1.4 Hz,1H). 1012 4-[[4-(4-cyanophenyl)- ESI-MS m/z ¹H NMR (400 MHz, DMSO-d6) δ2-fluoro-6-[2- calc. 569.14, 11.37 (s, 1H), 8.54 (d, J = 5.5 Hz,(trideuteriomethoxy)-4- found 570.2 1H), 8.31 (d, J = 2.2 Hz, 1H), 8.13(trifluoromethoxy)phe- (M + 1)+; (d, J = 3.0 Hz, 1H), 7.94 (d, J = 8.2noxy]benzoyl]amino]pyr- Retention time Hz, 2H), 7.83 (d, J = 8.3 Hz,3H), idine-2-carboxamide (Method B): 7.66 (d, J = 2.9 Hz, 1H), 7.59 (d,J = 1.98 minutes. 10.1 Hz, 1H), 7.27 (d, J = 8.8 Hz, 1H), 7.16 (d, J =2.8 Hz, 1H), 6.97 (d, J = 10.5 Hz, 2H).

Example 2034-[[2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-[4-(trifluoromethyl)cyclohexen-1-yl]benzoyl]amino]pyridine-2-carboxamide(1013)

Step 1: methyl4-bromo-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoate

Methyl 4-bromo-2,6-difluoro-benzoate (6.1 g, 24 mmol),2-methoxy-4-(trifluoromethoxy)phenol (5.2 g, 25 mmol) and Cs₂CO₃ (6.3 g,19 mmol) in DMF (74 mL) were stirred at 80° C. for 1 hour in a sealedvial. The reaction mixture was cooled to RT, diluted with ethyl acetate(150 mL) and washed with brine (3×). The organic layer was dried overNa₂SO₄, filtered and concentrated in vacuo. Silica gel chromatography(ethyl acetate/hexanes gradient) provided methyl4-bromo-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoate (9.23g, 87%) as a clear oil. ¹H NMR (400 MHz, DMSO-d6) δ 7.47 (dd, J=9.0, 1.6Hz, 1H), 7.29-7.21 (m, 2H), 7.04-6.96 (m, 1H), 6.73 (d, J=2.1 Hz, 1H),3.83 (s, 3H), 3.80 (s, 3H) ppm.

Step 2:4-bromo-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoic acid

To a slurry of methyl4-bromo-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoate (6.0g, 13.7 mmol) in methanol (60 mL) and water (60 mL) was added NaOH (5.5g, 138 mmol). The reaction mixture was stirred at RT for 5 hours. Thesolvent was evaporated and the residue was taken up in water, cooled inan ice bath and acidified by slow addition of 6 M HCl (pH˜ 2). Theresulting solid was filtered and washed with water. The solid was thendissolved in dichloromethane/ethyl acetate, dried over MgSO₄, filteredand concentrated. The above filtrate was extracted by ethyl acetate,dried over MgSO₄ and combined with above concentrate. The solution wasconcentrated in vacuo and dried under high vacuum to provide4-bromo-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoic acid(5.6 g, 96%) as clear oil. ESI-MS m/z calc. 423.96, found 427.0 (M+1)⁺;Retention time (Method B): 1.82 minutes.

Step 3:4-[[4-bromo-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide

To a solution of4-bromo-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoic acid(2.0 g, 4.7 mmol) and DMF (100 μL, 1.29 mmol) in dichloromethane (24 mL)at 0° C. under nitrogen was added oxalyl chloride (3.3 mL, 38 mmol). Thereaction was stirred at 0° C. for 10 minutes and allowed to warm to RTand stirred for 1 hour. The mixture was concentrated under reducedpressure and the residue was dissolved in NMP (5 mL). This solution wasadded dropwise to a suspension of 4-aminopyridine-2-carboxamide (700 mg,5.10 mmol) in DMF (720 μL), DIEA (5 mL, 29 mmol) and NMP (10 mL) undernitrogen atmosphere at 0° C. The resulting reaction mixture was slowlywarmed to room temperature and stirred for 18 hours. The reactionmixture was partitioned between water and ethyl acetate. The phases wereseparated and the aqueous layer was extracted with ethyl acetate. Thecombined organic layers were washed with water (2×) and brine, driedover Na₂SO₄, filtered and concentrated. Silica gel chromatography (ethylacetate/hexanes gradient) provided4-[[4-bromo-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(710 mg, 28%) as a white solid. ESI-MS m/z calc. 543.01, found 546.1(M+1)⁺; Retention time (Method B): 1.72 minutes. ¹H NMR (400 MHz,DMSO-d6) δ 11.30 (s, 1H), 8.54 (d, J=5.5 Hz, 1H), 8.29 (d, J=2.1 Hz,1H), 8.10 (d, J=2.8 Hz, 1H), 7.82 (dd, J=5.5, 2.2 Hz, 1H), 7.65 (d,J=2.8 Hz, 1H), 7.52 (dd, J=8.6, 1.6 Hz, 1H), 7.30 (d, J=8.8 Hz, 1H),7.20 (d, J=2.7 Hz, 1H), 7.05-6.97 (m, 1H), 6.75 (d, J=1.6 Hz, 1H), 3.78(s, 3H) ppm.

Step 4:4-[[2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-[4-(trifluoromethyl)cyclohexen-1-yl]benzoyl]amino]pyridine-2-carboxamide(1013)

A vial charged with4-[[4-bromo-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(25 mg, 0.046 mmol),4,4,5,5-tetramethyl-2-[4-(trifluoromethyl)cyclohexen-1-yl]-1,3,2-dioxaborolane(25 mg, 0.092 mmol), K₂CO₃ (13 mg, 0.092 mmol), and Pd(dppf)Cl₂.DCM (8mg, 0.009 mmol) in dioxane (500 μL) and water (50 μL) was flushed withnitrogen and heated at 100° C. for 16 hours. The reaction mixture wasfiltered and purified by HPLC (1-99% CH₃CN/5 mM HCl) to provide4-[[2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-[4-(trifluoromethyl)cyclohexen-1-yl]benzoyl]amino]pyridine-2-carboxamide(21.3 mg, 76%). ESI-MS m/z calc. 613.15, found 614.3 (M+1)⁺; Retentiontime (Method B): 2.01 minutes. ¹H NMR (400 MHz, DMSO-d6) δ 11.22 (s,1H), 8.52 (d, J=5.5 Hz, 1H), 8.29 (d, J=2.2 Hz, 11), 8.09 (d, l=2.9 Hz,1-), 7.81 (dd, =5.5, 2.2 Hz, H1), 7.64 (d, J=2.9 Hz, 1H), 7.24-7.14 (m,3H), 6.97 (dd, J=9.2, 2.3 Hz, 1H), 6.61 (s, 1H), 6.17 (s, 1H), 3.77 (s,3H), 2.40 (d, J=7.3 Hz, 3H), 2.28-2.09 (m, 2H), 2.03 (d, B=12.4 Hz, 1H),1.55 (td, =12.4, 6.0 Hz, 1H) ppm.

The compounds set forth in Table 103 were prepared by methods analogousto the preparation of compound 1013.

TABLE 103 Additional Compounds Prepared by Methods Analogous to Example203. Cmpd No. Compound Name LC/MS NMR (shifts in ppm) 1014 4-[[4-(2-ESI-MS m/z ¹H NMR (400 MHz, DMSO-d6) δ bicyclo[2.2.1]hept-2- calc.603.16, 11.24 (s, 1H), 8.52 (d, J = 5.5 Hz, enyl)-2-fluoro-6-[2- found604.3 1H), 8.30 (d, J = 2.2 Hz, 1H), 8.10 methoxy-4- (M + 1)+; (d, J =2.9 Hz, 1H), 7.82 (dd, J = (trifluoromethoxy)phe- Retention time 5.5,2.2 Hz, 1H), 7.65 (d, J = 2.9 noxy]benzoyl]amino]pyr- (Method B): Hz,1H), 7.25-7.13 (m, 3H), 7.01- idine-2-carboxamide 1.69 minutes. 6.94 (m,1H), 6.60 (s, 1H), 6.04 (d, J = 4.2 Hz, 1H), 3.90 (s, 4H), 3.77 (s, 3H),2.42 (d, J = 7.4 Hz, 2H), 2.37-2.31 (m, 2H), 1.77 (t, J = 6.5 Hz, 2H).1015 4-[[4-(1,4- ESI-MS m/z ¹H NMR (400 MHz, DMSO-d6) δdioxaspiro[4.5]dec-7- calc. 557.16, 11.25 (s, 1H), 8.52 (d, J = 5.5 Hz,en-8-yl)-2-fluoro-6-[2- found 558.2 1H), 8.30 (d, J = 2.1 Hz, 1H), 8.11methoxy-4- (M + 1)+; (s, 1H), 7.82 (dd, J = 5.8, 2.1 Hz,(trifluoromethoxy)phe- Retention time 1H), 7.66 (s, 1H), 7.27-7.13 (m,noxy]benzoyl]amino]pyr- (Method B): 3H), 6.97 (d, J = 8.7 Hz, 1H), 6.60idine-2-carboxamide 2.01 minutes. (s, 1H), 6.05 (s, 1H), 3.89 (s, 4H),3.76 (s, 3H), 2.43 (s, 2H), 2.34 (s, 2H), 1.77 (t, J = 6.4 Hz, 2H). 10164-[[4-(4-tert- ESI-MS m/z ¹H NMR (400 MHz, DMSO-d6) δbutylcyclohexen-1-yl)- calc. 601.22, 11.23 (s, 1H), 8.52 (d, J = 5.5 Hz,2-fluoro-6-[2-methoxy- found 602.3 1H), 8.30 (s, 1H), 8.17-8.07 (m, 4-(M + 1)+; 1H), 7.86-7.79 (m, 1H), 7.70- (trifluoromethoxy)phe- Retentiontime 7.57 (m, 1H), 7.21 (d, J = 8.8 Hz, noxy]benzoyl]amino]pyr- (MethodB): 1H), 7.19-7.11 (m, 2H), 6.98 (d, idine-2-carboxamide 2.34 minutes. J= 8.8 Hz, 1H), 6.57 (s, 1H), 6.19 (s, 1H), 3.76 (s, 3H), 2.40-2.12 (m,3H), 1.99-1.80 (m, 2H), 1.32- 1.09 (m, 2H), 0.86 (s, 9H).

Example 2044-[[2-fluoro-4-(4-methoxycyclohexyl)-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(1017)

4-[[2-fluoro-4-(4-methoxycyclohexen-1-yl)-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(1009, Table 102) (9 mg, 0.016 mmol) was dissolved in ethyl acetate (250μL) and methanol (250 μL) and treated with 10% Pd/C palladium (1 mg,0.009 mmol). The mixture was degassed with a flow of nitrogen for 2minutes, then flushed with hydrogen (balloon). The reaction mixture wasstirred at RT for 16 hours, then filtered and purified by HPLC (1-99%CH₃CN/5 mM HCl) to provide the two separated diastereomers assigned asdiastereomer 1 and diastereomer 2, respectively based on HPLC elutionorder. It is appreciated that both diastereomers of4-[[2-fluoro-4-(4-methoxycyclohexyl)-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(17) were isolated and that those diastereomers have the structure ofcompounds 1017-a and 1017-b (above). However, the relativestereochemistry of diastereomers 1 and 2 was not determined.

Diastereomer 1:4-[[2-fluoro-4-(4-methoxycyclohexyl)-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(1017) (1.3 mg, 14%). ESI-MS m/z calc. 580.20, found 581.4 (M+1)⁺;Retention time (Method B): 1.74 minutes.

Diastereomer 2:4-[[2-fluoro-4-(4-methoxycyclohexyl)-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(1017) (5.0 mg, 55%). ESI-MS m/z calc. 580.20, found 581.3 (M+1)⁺;Retention time (Method B): 1.82 minutes. 1H NMR (400 MHz, DMSO-d₆) δ11.25 (s, 1H), 8.52 (d, J=5.5 Hz, 1H), 8.32 (d, J=2.1 Hz, 1H), 8.11 (s,1H), 7.82 (dd, J=5.7, 2.1 Hz, 1H), 7.67 (s, 1H), 7.23 (d, J=8.8 Hz, 1H),7.19 (d, J=2.7 Hz, 1H), 7.03-6.97 (m, 1H), 6.95 (d, J=10.1 Hz, 1H), 6.40(s, 1H), 3.42-3.39 (m, 1H), 3.20 (s, 3H), 2.61-2.56 (m, 1H), 2.03-1.80(m, 2H), 1.68-1.30 (m, 6H).

The compounds set forth in Table 104 were prepared by methods analogousto the preparation of compound 1017

TABLE 104 Additional Compounds Prepared by Methods Analogous to Example204 Cmpd No. Compound Name LC/MS NMR (shifts in ppm) 10184-[[2-fluoro-4- ESI-MS m/z ¹H NMR (400 MHz, DMSO-d6) δ 11.23 (s,tetrahydrofuran-3-yl-6- calc. 538.16, 1H), 8.52 (d, J = 5.5 Hz, 1H),8.30 (d, J = 2.1 [2- found 539.2 Hz, 1H), 8.10 (d, J = 2.9 Hz, 1H), 7.81(dd, (trideuteriomethoxy)-4- (M + 1)+; J = 5.6, 2.2 Hz, 1H), 7.65 (d, J= 2.8 Hz, 1H), (trifluoromethoxy)phe- Retention time 7.22 (d, J = 8.7Hz, 1H), 7.17 (d, J = 2.8 Hz, noxy]benzoyl]amino]pyr- (Method B): 1H),7.07 (d, J = 10.1 Hz, 1H), 7.02-6.95 idine-2-carboxamide 1.53 minutes.(m, 1H), 6.52 (s, 1H), 3.93 (t, J = 7.7 Hz, 1H), 3.86 (dd, J = 8.3, 4.8Hz, 1H), 3.73 (q, J = 7.7 Hz, 1H), 3.50 (dd, J = 8.3, 6.8 Hz, 1H),3.44-3.37 (m, 1H), 2.32-2.19 (m, 1H), 1.90-1.75 (m, 1H). 10194-[[2-fluoro-4- ESI-MS m/z ¹H NMR (400 MHz, DMSO-d6) δ 11.24 (s,tetrahydropyran-4-yl-6- calc. 552.17, 1H), 8.52 (d, J = 5.5 Hz, 1H),8.31 (d, J = 2.1 [2- found 553.2 Hz, 1H), 8.10 (d, J = 2.7 Hz, 1H), 7.82(dd, (trideuteriomethoxy)-4- (M + 1)+; J = 5.6, 2.2 Hz, 1H), 7.66 (d, J= 2.8 Hz, 1H), (trifluoromethoxy)phe- Retention time 7.23 (d, J = 8.8Hz, 1H), 7.18 (d, J = 2.7 Hz, noxy]benzoyl]amino]pyr- (Method B): 1H),7.06 (d, J = 10.2 Hz, 1H), 7.02-6.92 idine-2-carboxamide 1.58 minutes.(m, 1H), 6.49 (s, 1H), 3.98-3.82 (m, 2H), 3.39 (m, 2H, partiallyobscured by H2O peak), 2.78 (dq, J = 10.4, 5.7 Hz, 1H), 1.69- 1.49 (m,4H). 1020 4-[[2-fluoro-6-[2- ESI-MS m/z ¹H NMR (400 MHz, DMSO-d6) δ11.20 (s, methoxy-4- calc. 559.17, 1H), 8.52 (d, J = 5.5 Hz, 1H), 8.31(d, J = 2.1 (trifluoromethoxy)phe- found 560.3 Hz, 1H), 8.09 (d, J = 2.9Hz, 1H), 7.83 (dd, noxy]-4-norboman-2-yl- (M + 1)+; J = 5.7, 2.2 Hz,1H), 7.64 (s, 1H), 7.23 (d, J = benzoyl]amino]pyridine- Retention time8.8 Hz, 1H), 7.18 2-carboxamide (Method B): (d, J = 2.7 Hz, 1H), 6.98(t, J = 9.6 Hz, 2H), 2.03 minutes. 6.37 (s, 1H), 3.76 (s, 3H), 3.18 (d,J = 11.9 Hz, 1H), 2.29 (s, 1H), 2.24 (s, 1H), 1.86 (t, J = 12.4 Hz, 1H),1.49 (t, J = 10.3 Hz, 2H), 1.35 (d, J = 9.3 Hz, 1H), 1.29-1.12 (m, 2H),1.10-0.99 (m, 2H).

Example 2054-[[2-fluoro-4-(4-methylpent-1-ynyl)-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(1021)

In a 4-mL vial was combined4-[[4-bromo-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(30 mg, 0.055 mmol) and TEA (100 μL, 0.7175 mmol). The mixture wasbubbled with nitrogen for 15 minutes. To this suspension, was addedcopper (I) iodide (2 mg, 0.01 mmol) followed by Pd(Ph₃)₄ (7 mg, 0.006mmol). The resulting mixture was stirred for 5 minutes under nitrogen.4-Methylpent-1-yne (50 μL, 0.42 mmol) was then added and the reactionmixture stirred at 92° C. for 1 hour. The mixture was cooled to RT,filtered and purified by HPLC (1-99% CH₃CN/5 mM HCl) to provide4-[[2-fluoro-4-(4-methylpent-1-ynyl)-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(23 mg, 77%). ESI-MS m/z calc. 548.18, found 549.3 (M+1)⁺; Retentiontime (Method B): 2.04 minutes. ¹H NMR (400 MHz, DMSO-d6) δ 11.28 (s,1H), 8.53 (d, J=5.5 Hz, 1H), 8.30 (d, J=2.1 Hz, 1H), 8.09 (d, J=2.8 Hz,1H), 7.82 (dd, J=5.5, 2.2 Hz, 1H), 7.65 (d, J=2.8 Hz, 1H), 7.28 (d,J=8.9 Hz, 1H), 7.22-7.13 (m, 2H), 7.01 (ddd, J=8.8, 2.7, 1.2 Hz, 1H),6.48 (d, J=1.3 Hz, 1H), 2.31 (d, J=6.5 Hz, 2H), 1.82 (dp, J=13.2, 6.6Hz, 1H), 0.96 (d, J=6.6 Hz, 6H) ppm.

The compounds set forth in Table 105 were prepared by methods analogousto the preparation of compound 1021.

TABLE 105 Additional Compounds Prepared by Methods Analogous to Example205. Cmpd No. Compound Name LC/MS NMR (shifts in ppm) 10224-[[4-(3,3-dimethylbut- ESI-MS m/z ¹H NMR (400 MHz, DMSO-d6) δ1-ynyl)-2-fluoro-6-[2- calc. 548.17621, 11.27 (s, 1H), 8.53 (d, J = 5.5Hz, (trideuteriomethoxy)-4- found 549.3 1H), 8.30 (d, J = 2.1 Hz, 1H),8.09 (trifluoromethoxy)phe- (M + 1)+; (d, J = 2.9 Hz, 1H), 7.82 (dd, J =noxy]benzoyl]amino]pyr- Retention time 5.5, 2.2 Hz, 1H), 7.65 (d, J =2.8 idine-2-carboxamide (Method B): Hz, 1H), 7.28 (d, J = 8.8 Hz, 1H),2.03 minutes. 7.22-7.10 (m, 2H), 7.00 (ddt, J = 8.8, 2.4, 1.3 Hz, 1H),6.46 (d, J = 1.3 Hz, 1H), 1.25 (s, 9H). 1023 4-[[4-(2- ESI-MS m/z ¹H NMR(400 MHz, DMSO-d6) δ cyclopropylethynyl)-2- calc. 532.14491, 11.31 (s,1H), 8.53 (d, J = 5.4 Hz, fluoro-6-[2- found 533.2 1H), 8.31 (s, 1H),8.12 (s, 1H), 7.86- (trideuteriomethoxy)-4- (M + 1)+; 7.78 (m, 1H), 7.67(s, 1H), 7.28 (trifluoromethoxy)phe- Retention time (d, J = 8.7 Hz, 1H),7.19 (s, 1H), noxy]benzoyl]amino]pyr- (Method B): 7.14 (d, J = 9.5 Hz,1H), 7.00 (d, J = idine-2-carboxamide 1.85 minutes. 8.9 Hz, 1H), 6.46(s, 1H), 1.60- 1.48 (m, 1H), 0.94-0.83 (m, 2H), 0.78-0.71 (m, 2H). 10244-[[4-(2- ESI-MS m/z ¹H NMR (400 MHz, DMSO-d6) δ cyclobutylethynyl)-2-calc. 546.16056, 11.32 (s, 1H), 8.53 (d, J = 5.4 Hz, fluoro-6-[2- found547.3 1H), 8.31 (s, 1H), 8.11 (s, 1H), 7.82 (trideuteriomethoxy)-4- (M +1)+; (d, J = 5.4 Hz, 1H), 7.67 (s, 1H), (trifluoromethoxy)phe- Retentiontime 7.29 (d, J = 8.7 Hz, 1H), 7.23-7.12 noxy]benzoyl]amino]pyr- (MethodB): (m, 2H), 7.01 (d, J = 8.8 Hz, 1H), idine-2-carboxamide 2.0 minutes.6.48 (s, 1H), 3.31-3.19 (m, 1H), 2.31-2.20 (m, 2H), 2.17-2.04 (m, 2H),2.00-1.74 (m, 2H).

Example 2064-[[6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methylsulfanyl-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(1025)

Step 1: 1-bromo-2-methoxy-4-(trifluoromethoxy)benzene

A 500-mL 3-neck round-bottom flask was fitted with a mechanical stirrer,a cooling bath, an addition funnel, temperature probe and a nitrogeninlet/outlet. The vessel was charged under a nitrogen atmosphere with2-bromo-5-(trifluoromethoxy)phenol (80 g, 311 mmol) and DMF (800 mL)then treated with K₂CO₃ (56.05 g, 405.6 mmol). The mixture was stirredat RT for 15 minutes and then cooled in an ice bath. Methyl iodide (19.4mL, 311 mmol) was added dropwise over 5 minutes. The cooling bath wasremoved and the resulting suspension was allowed to slowly warm to roomtemperature and continued to stir for 10 hours. The reaction mixture wasthen poured into crushed ice/water (1000 mL) and stirred for 5 minutes.The mixture was diluted with methyl tert-butyl ether (1000 mL) andtransferred to a separatory funnel and allowed to stand for 10 minutes.The organic phase was separated and the aqueous was extracted withmethyl tert-butyl ether (2×500 mL). The combined organic phases werewashed with brine, dried over Na₂SO₄, filtered and concentrated. Silicagel chromatography (starting with hexane, then 9:1hexane:dichloromethane and finally 8:1:1 hexane:dichloromethane:ethylacetate) provided 1-bromo-2-methoxy-4-(trifluoromethoxy)benzene (82 g,97%) as a pale yellow oil. ¹H NMR (400 MHz, DMSO-d6) δ 7.71 (d, J=8.7Hz, 1H), 7.25-7.06 (m, 1H), 6.93 (ddq, J=8.7, 2.5, 1.2 Hz, 1H), 3.89 (s,3H) ppm.

Step 2: 2-methoxy-4-(trifluoromethoxy)phenol

A 1000-mL 3-neck round-bottom flask was fitted with a mechanicalstirrer, a heating mantle, a water cooled reflux condenser, atemperature probe/controller and a nitrogen inlet/outlet. The vessel wascharged under a nitrogen atmosphere with tetrabutylammonium hydroxide(287 mL of 40% w/v, 443 mmol) in water and1-bromo-2-methoxy-4-(trifluoromethoxy)benzene (30.0 g, 111 mmol). Thesolution was degassed with nitrogen for 15 minutes with stirring. Thevessel was then charged with 1,10-phenanthroline-4,7-diol (2.349 g,11.07 mmol) added as a solid in one portion followed by copper (I) oxide(792 mg, 5.54 mmol) added as a solid in one portion. After theseadditions the gas dispersion tube was removed and the vessel was fittedwith a septum. The mixture was then heated to a pot temperature of 100°C. for 15 hours. After cooling to RT the reaction mixture was pouredinto ice cold hydrochloric acid (554 mL of 1 M HCl, 554 mmol). Themixture was diluted with ethyl acetate (500 mL) and mixed for severalminutes. The biphasic mixture was transferred to a separatory funnel andallowed to stand for 5 minutes. The phases were separated and theaqueous was extracted with ethyl acetate (2×200 mL). The combinedorganic phases were washed with brine (2×250 mL), dried over Na₂SO₄,filtered and concentrated. Silica gel chromatography (ethylacetate/hexanes gradient) provided 2-methoxy-4-(trifluoromethoxy)phenol(18 g, 78%) as a pale yellow oil. LC/MS retention time (Method B): 1.34minutes. ¹H NMR (400 MHz, DMSO-d6) δ 9.35 (s, 1H), 6.92 (dd, J=2.7, 0.8Hz, 1H), 6.82 (d, J=8.6 Hz, 1H), 6.79-6.70 (m, 1H), 3.79 (s, 3H) ppm.

Step 3:2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoicacid

A pressure flask was charged with6-bromo-2-fluoro-3-(trifluoromethyl)benzoic acid (5.0 g, 17.42 mmol),2-methoxy-4-(trifluoromethoxy)phenol (4.35 g, 20.90 mmol), Cs₂CO₃ (11.35g, 34.84 mmol) and toluene (50 mL). The mixture was degassed withnitrogen. After approximately 2 minutes, copper (I) iodide (663 mg, 3.48mmol) was added and the reaction was stirred at 100° C. for 1 hour. Thereaction was diluted with 300 mL ethyl acetate and 200 mL of water andthe phases were separated. The aqueous layer was acidified to pH-3 andextracted with ethyl acetate. The combined organic phases were driedover Na₂SO₄, filtered and concentrated. The residue was purified bysilica gel chromatography (ethyl acetate/hexanes gradient, followed by1:9 methanol/dichloromethane) to afford2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoicacid (5.45 g, 76%) as a pale green solid. ESI-MS m/z calc. 414.03, found415.0 (M+1)⁺; retention time (Method B): 1.94 minutes. ¹H NMR (400 MHz,DMSO-d6) δ 7.53 (t, J=8.4 Hz, 1H), 7.27-7.11 (m, 2H), 6.99 (ddd, J=8.8,2.7, 1.3 Hz, 1H), 6.49 (d, J=8.8 Hz, 1H), 3.80 (s, 3H) ppm.

Step 4:4-[[2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide

A microwave vial charged with4-[(Z)-[(tert-butylamino)-phenylsulfanyl-methylene]amino]pyridine-2-carboxamide(75 mg, 0.29 mmol, prepared as described in Example 201),tris[(Z)-1-methyl-3-oxo-but-1-enoxy]iron (2 mg, 0.006 mmol) and2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoicacid (94 mg, 0.29 mmol) in isopropanol (2 mL) was heated at 83° C. for16 hours. The reaction mixture was cooled to room temperature and thesolvent evaporated. The crude material was taken up in dichloromethaneand washed with 1N HCl. The organic layer was dried over MgSO₄, filteredand concentrated. The residue was purified by silica gel chromatography(ethyl acetate/hexanes gradient) to afford4-[[2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(80 mg, 64%). ESI-MS m/z calc. 533.08, found 534.1 (M+1)⁺; Retentiontime (Method B): 1.77 minutes. ¹H NMR (400 MHz, DMSO-d6) δ 11.45 (s,1H), 8.56 (d, J=5.5 Hz, 1H), 8.32 (d, J=2.2 Hz, 1H), 8.12 (d, J=2.7 Hz,1H), 7.86-7.77 (m, 2H), 7.72-7.64 (m, 1H), 7.38 (d, J=8.8 Hz, 1H), 7.27(d, J=2.8 Hz, 1H), 7.08-7.01 (m, 1H), 6.68 (d, J=8.9 Hz, 1H), 3.79 (s,3H) ppm.

Step 5:4-[[6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methylsulfanyl-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(1025)

A solution of4-[[2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(100 mg, 0.187 mmol) and sodium methylthiol (13 mg, 0.19 mmol) in THF (2mL) was heated at 60° C. for 24 hours. The mixture was cooled RT andpartitioned between ethyl acetate and water. The layers were separatedand the organic layer was washed with water (3×) and brine, dried overNa₂SO₄, filtered and concentrated. Silica gel chromatography(methanol/dichloromethane gradient) provided4-[[6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-methylsulfanyl-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(27 mg, 23%) as a white solid. ESI-MS m/z calc. 561.08, found 562.44(M+1)⁺; Retention time (Method B): 1.85 minutes. ¹H NMR (400 MHz,DMSO-d6) δ 11.21 (s, 1H), 8.54 (d, J=5.5 Hz, 1H), 8.37 (d, J=2.1 Hz,1H), 8.09 (d, J=2.9 Hz, 1H), 7.90-7.78 (m, 2H), 7.65 (d, J=2.9 Hz, 1H),7.36-7.20 (m, 2H), 7.04 (ddd, J=8.8, 2.8, 1.3 Hz, 1H), 6.85 (d, J=8.9Hz, 1H), 3.80 (s, 3H), 2.45 (s, 3H) ppm.

Example 2074-[[6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-(oxetan-3-yloxy)-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(1026)

Oxetan-3-ol (21 mg, 0.28 mmol) and finely-ground potassium carbonate (31mg, 0.22 mmol) were added to a solution of4-[[2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(30 mg, 0.056 mmol) in DMSO (0.5 mL) and the mixture stirred at 140° C.for 30 minutes in a sealed vial. The reaction mixture was filtered andpurified by HPLC (1-99% CH₃CN/5 mM HCl) to provide4-[[6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-(oxetan-3-yloxy)-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(1.5 mg, 5%). ESI-MS m/z calc. 587.11, found 588.1 (M+1)⁺; Retentiontime (Method B): 1.75 minutes.

The compounds set forth in Table 106 were prepared by methods analogousto the preparation of compound 1026.

TABLE 106 Additional Compounds Prepared by Methods Analogous to Example207. Cmpd No. Compound Name LC/MS NMR (shifts in ppm) 1027 4-[[2-[2-ESI-MS m/z ¹H NMR (400 MHz, DMSO-d6) δ 11.69 (s, (dimethylamino)ethoxy]-calc. 602.16, 1H), 10.46 (s, 1H), 8.57 (s, 1H), 8.44 (s, 6-[2-methoxy-4-found 603.2 1H), 8.21 (s, 1H), 7.94 (s, 1H), 7.81-7.66(trifluoromethoxy)phe- (M + 1)+; (m, 2H), 7.43 (d, J = 8.7 Hz, 1H), 7.25(d, noxy]-3- Retention time J = 2.7 Hz, 1H), 7.05 (d, J = 8.7 Hz, 1H),6.60 (trifluoromethyl)benzo- (Method B): (d, J = 8.9 Hz, 1H), 4.46 (s,2H), 3.78 (s, yl]amino]pyridine-2- 1.37 minutes. 3H, partially obscuredby water peak), 3.44 carboxamide (d, J = 5.5 Hz, 2H), 2.77 (d, J = 4.6Hz, 6H). 1028 4-[[2-(2- ESI-MS m/z ¹H NMR (400 MHz, DMSO-d6) δ 11.38 (s,cyclopropylethoxy)-6- calc. 599.15, 1H), 8.60 (d, J = 5.4 Hz, 1H), 8.42(d, J = [2-methoxy-4- found 600.3 2.4 Hz, 1H), 8.17 (s, 1H), 7.94-7.88(m, (trifluoromethoxy)phe- (M + 1)+; 1H), 7.80-7.67 (m, 2H), 7.36 (d, J= 8.9 noxy]-3- Retention time Hz, 1H), 7.29 (s, 1H), 7.08 (d, J = 8.8Hz, (trifluoromethyl)benzo- (Method B): 1H), 6.58 (d, J = 9.0 Hz, 1H),4.18 (t, J = yl]amino]pyridine-2- 2.05 minutes. 6.5 Hz, 2H), 3.84 (d, J= 2.4 Hz, 3H), 1.57 carboxamide (d, J = 6.8 Hz, 2H), 0.83-0.67 (m, 1H),0.30 (d, J = 7.7 Hz, 2H), 0.00 (d, J = 4.9 Hz, 2H).

Example 2084-[[2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-[4-(trifluoromethyl)cyclohexen-1-yl]benzoyl]amino]pyridine-2-carboxamide(1029)

Step 1: 4-bromo-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzaldehyde

To a stirring solution of 4-bromo-2-fluoro-benzaldehyde (3.70 g, 18.2mmol) in DMF (35 mL) was added Cs₂CO₃ (7.50 g, 23.0 mmol) and2-methoxy-4-(trifluoromethoxy)phenol (4.17 g, 20.0 mmol). The reactionmixture was stirred at RT for 16 hours, and then partitioned betweenethyl acetate and water. The organic layer was washed with water, 50%saturated aqueous NaHCO₃ and brine, then dried over MgSO₄, filtered andconcentrated in vacuo. Silica gel chromatography (ethyl acetate/hexanesgradient) provided4-bromo-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzaldehyde (6.77 g,95%). ESI-MS m/z calc. 389.97, found 392.9 (M+1)⁺; Retention time(Method A): 0.8 minutes. ¹H NMR (400 MHz, DMSO-d6) δ 10.43 (s, 1H), 7.75(d, J=8.3 Hz, 1H), 7.48-7.43 (m, 1H), 7.40 (d, J=8.8 Hz, 1H), 7.28 (d,J=2.7 Hz, 1H), 7.05 (ddd, J=8.8, 2.8, 1.3 Hz, 1H), 6.88 (d, J=1.7 Hz,1H), 3.80 (s, 3H) ppm.

Step 2: 4-bromo-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoic acid

A mixture of4-bromo-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzaldehyde (6.74 g,17.2 mmol) and sodium dihydrogenphosphate (3.10 g, 25.8 mmol) intert-butyl alcohol (60 mL), water (35 mL), and acetonitrile (35 mL) at0° C. was treated with 2-methylbut-2-ene (8.0 mL, 75 mmol) followed bythe portion-wise addition of sodium chlorite (2.92 g, 25.8 mmol) over 10minutes. The mixture was allowed to warm to RT and stirred for 16 hours.Additional sodium dihydrogenphosphate (3.10 g, 25.8 mmol) and sodiumchlorite (2.92 g, 25.8 mmol) were added and the reaction mixture stirredfor 30 minutes. The reaction mixture was acidified to pH˜1-2 usingaqueous HCl (175 mL of 1 M, 175 mmol) and partitioned with ethylacetate. The organic layer was washed with an aqueous sodium sulfitesolution to remove the faint yellow color. The two layers were separatedand the combined aqueous layers extracted with ethyl acetate (3×25 mL).The combined organics were washed with brine, dried over Na₂SO₄,filtered and concentrated. The resulting solid was triturated withhexanes (100 mL) and filtered to provide4-bromo-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoic acid (6.70 g,96%) as a white solid. ESI-MS m/z calc. 405.97, found 407.9 (M+1)⁺;Retention time (Method A): 0.72 minutes. ¹H NMR (400 MHz, DMSO-d6) δ13.03 (s, 1H), 7.75 (d, J=8.4 Hz, 1H), 7.39 (dd, J=8.3, 1.8 Hz, 1H),7.21 (d, J=2.7 Hz, 1H), 7.09 (d, J=8.8 Hz, 1H), 6.99-6.94 (m, 1H), 6.88(d, J=1.8 Hz, 1H), 3.80 (s, 3H) ppm.

Step 3:4-[[4-bromo-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide

A solution of 4-bromo-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoicacid (2.01 g, 4.94 mmol) and DMF (20 μL, 0.26 mmol) in anhydrousdichloromethane (16 mL) under nitrogen at 0° C. was treated dropwisewith oxalyl chloride (700 μL, 8.02 mmol). The solution was stirred for15 minutes and then at 35° C. for 15 minutes (until no further gasevolution was observed). The reaction mixture was concentrated in vacuoand dried under high vacuum for 10 minutes. The resulting solid wasdissolved in dichloromethane (5 mL) and the solution was added dropwiseto a solution of 4-aminopyridine-2-carboxamide (0.812 g, 5.92 mmol) andDIEA (2.2 mL, 13 mmol) in NMP (20 mL) at 0° C. The reaction mixture wasremoved from the ice bath and stirred at RT for 2 hours. Thedichloromethane was removed from the reaction mixture under reducedpressure and the reaction mixture diluted with ethyl acetate and washedwith water (2×), 50% aqueous saturated NaHCO₃ and brine. The organicphase was dried over Na₂SO₄, filtered and concentrated in vacuo. Theresulting solid was triturated with cold dichloromethane (25 mL) andfiltered. The solid was rinsed with minimal cold dichloromethane and airdried to provide4-[[4-bromo-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(1.21 g, 47%). ESI-MS m/z calc. 525.02, found 527.0 (M+1)⁺; Retentiontime (Method A): 0.71 minutes. ¹H NMR (400 MHz, DMSO-d6) δ 10.88 (s,1H), 8.51 (d, J=5.5 Hz, 1H), 8.30 (d, J=2.1 Hz, 1H), 8.08 (d, J=2.9 Hz,1H), 7.85 (dd, J=5.5, 2.1 Hz, 1H), 7.64 (d, J=8.1 Hz, 2H), 7.45 (dd,J=8.2, 1.7 Hz, 1H), 7.31 (d, J=8.8 Hz, 1H), 7.19 (d, J=2.6 Hz, 1H),7.05-6.97 (m, 1H), 6.93 (d, J=1.7 Hz, 1H), 3.77 (s, 3H) ppm.

Step 4:4-[[2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-[4-(trifluoromethyl)cyclohexen-1-yl]benzoyl]amino]pyridine-2-carboxamide(1029)

A vial charged with4-[[4-bromo-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(30 mg, 0.057 mmol),4,4,5,5-tetramethyl-2-[4-(trifluoromethyl)cyclohexen-1-yl]-1,3,2-dioxaborolane(31 mg, 0.11 mmol), K₂CO₃ (8 mg, 0.06 mmol) and Pd(dppf)Cl₂.DCM (5 mg,0.006 mmol) in dioxane (500 μL) and water (50 μL) was flushed withnitrogen and heated at 100° C. for 16 hours. The reaction mixture wasfiltered and purified by HPLC (1-99% CH₃CN/5 mM HCl) to provide4-[[2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-[4-(trifluoromethyl)cyclohexen-1-yl]benzoyl]amino]pyridine-2-carboxamide(33 mg, 97%). ESI-MS m/z calc. 595.15, found 596.2 (M+1)⁺; Retentiontime (Method B): 2.07 minutes. ¹H NMR (400 MHz, DMSO-d6) δ 10.77 (s,1H), 8.49 (d, J=5.5 Hz, 1H), 8.29 (d, J=2.1 Hz, 1H), 8.07 (s, 1H), 7.84(dd, J=5.5, 2.2 Hz, 1H), 7.67 (d, J=8.1 Hz, 1H), 7.62 (s, 1H), 7.54 (s,1H), 7.32 (d, J=8.3 Hz, 1H), 7.19-7.12 (m, 2H), 6.96 (d, J=8.8 Hz, 1H),6.85 (s, 1H), 3.76 (s, 3H), 2.11-1.86 (m, 4H), 1.65-1.47 (m, 1H),1.39-1.24 (m, 2H) ppm.

The compounds set forth in Table 107 were prepared by methods analogousto the preparation of compound 1029

TABLE 107 Additional Compounds Prepared by Methods Analogous to Example208. Cmpd No. Compound Name LC/MS NMR (shifts in ppm) 1030 4-[[4-(2,5-ESI-MS m/z ¹H NMR (400 MHz, DMSO-d6) δ 10.84 dihydrofuran-3-yl)-2- calc.515.13, (s, 1H), 8.49 (d, J = 5.4 Hz, 1H), 8.27 (d, [2-methoxy-4- found516.2 J = 2.4 Hz, 1H), 8.09 (s, 1H), 7.83 (dd, J =(trifluoromethoxy)phe- (M + 1)+; 5.6, 2.5 Hz, 1H), 7.70 (d, J = 8.0 Hz,1H), noxy]benzoyl]amino]pyr- Retention time 7.64 (s, 1H), 7.31 (d, J =8.0 Hz, 1H), idine-2-carboxamide (Method B): 7.14-7.06 (m, 2H),6.99-6.89 (m, 2H), 6.59 1.59 minutes. (s, 1H), 4.84 (br s, 2H), 4.72 (d,J = 5.5 Hz, 2H), 3.75 (s, 3H). 1031 4-[[4-(4- ESI-MS m/z ¹H NMR (400MHz, DMSO-d6) δ 10.78 methoxycyclohexen-1- calc. 557.18, (s, 1H), 8.50(d, J = 5.5 Hz, 1H), 8.30 (d, yl)-2-[2-methoxy-4- found 558.2 J = 2.2Hz, 1H), 8.10 (s, 1H), 7.85 (dd, J = (trifluoromethoxy)phe- (M + 1)+;5.4, 2.2 Hz, 1H), 7.65 (t, J = 6.2 Hz, 2H), noxy]benzoyl]amino]pyr-Retention time 7.31 (d, J = 8.1 Hz, 1H), 7.19-7.12 (m,idine-2-carboxamide (Method B): 2H), 6.96 (d, J = 9.3 Hz, 1H), 6.83 (s,1H), 1.81 minutes. 6.06 (s, 1H), 3.76 (s, 3H), 3.26 (s, 3H), 2.50 (m,3H), 2.37 (s, 1H), 2.12 (t, J = 11.8 Hz, 1H), 1.93 (d, J = 11.8 Hz, 1H),1.68 (dt, J = 13.4, 6.9 Hz, 1H).

Example 2094-[[4-(4-methoxycyclohexyl)-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(1032)

4-[[4-(4-Methoxycyclohexen-1-yl)-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(16 mg, 0.029 mmol) was dissolved in ethyl acetate (250 μL)/methanol(250 μL). The mixture was flushed with nitrogen then treated with 10%Pd/C (2 mg, 0.01879 mmol). The resulting mixture was degassed with aflow of nitrogen for 2 minutes, then purged with hydrogen. The reactionwas stirred at room temperature for 16 hours. The mixture was filteredand purified by phase HPLC (1-99% CH₃CN/5 mM HCl) to provide the twoseparated diastereomers, assigned as diastereomer 1 and diastereomer 2,respectively based on HPLC elution order. It is appreciated that bothdiastereomers of4-[[4-(4-methoxycyclohexyl)-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(1032) were isolated and that those diastereomers have the structure ofcompounds 1032-a and 1032-b (above). However, the relativestereochemistry of diastereomers 1 and 2 was not determined.

Diastereomer 1:4-[[4-(4-methoxycyclohexyl)-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(32) (2.4 mg, 15%). ESI-MS m/z calc. 559.19, found 560.2 (M+1)⁺;Retention time (Method B): 1.79 minutes. 1H NMR (400 MHz, DMSO-d₆) δ10.92 (s, 1H), 8.52 (d, J=5.7 Hz, 1H), 8.36 (s, 1H), 8.21 (s, 1H), 7.89(dd, J=5.7, 2.2 Hz, 1H), 7.75 (s, 1H), 7.61 (d, J=7.9 Hz, 1H), 7.26-7.15(m, 2H), 7.11 (d, 1H), 6.99 (d, 1H), 6.62 (s, 1H), 3.75 (s, 3H),3.49-3.38 (m, 1H), 3.21 (s, 3H), 2.58 (m, 1H, obscured by solvent peak),2.00-1.81 (m, 2H), 1.68-1.34 (m, 6H).

Diastereomer 2:4-[[4-(4-methoxycyclohexyl)-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide(32) (6.6 mg, 41%). ESI-MS m/z calc. 559.19, found 560.3 (M+1)⁺;Retention time (Method B): 1.89 minutes. 1H NMR (400 MHz, DMSO-d₆) δ10.78 (s, 1H), 8.48 (d, J=5.5 Hz, 1H), 8.29 (d, J=2.1 Hz, 1H), 8.08 (d,J=2.8 Hz, 1H), 7.84 (dd, J=5.5, 2.2 Hz, 1H), 7.72-7.50 (m, 2H),7.26-7.08 (m, 3H), 6.97 (dd, J=8.8, 1.7 Hz, 1H), 6.69 (d, J=1.4 Hz, 1H),3.75 (s, 3H), 3.23 (s, 3H), 3.20-3.07 (m, 1H), 2.48 (m, 1H, obscured bysolvent peak), 2.15-1.96 (m, 2H), 1.85-1.65 (m, 2H), 1.54-1.31 (m, 2H),1.31-1.09 (m, 2H).

The compounds set forth in Table 108 were prepared by methods analogousto the preparation of compound 1032

TABLE 108 Additional Compounds Prepared by Methods Analogous to Example209 Cmpd No. Compound Name LC/MS NMR (shifts in ppm) 10334-[[2-[2-methoxy-4- ESI-MS m/z ¹H NMR (400 MHz, DMSO-d6) δ 10.86(trifluoromethoxy)phe- calc. 517.15, (s, 1H), 8.51 (d, J = 5.5 Hz, 1H),8.32 (d, noxy]-4-tetrahydrofuran- found 518.2 J = 2.1 Hz, 1H), 8.15 (s,1H), 7.87 (dd, J = 3-yl- (M + 1)+; 5.6, 2.1 Hz, 1H), 7.69 (s, 1H), 7.64(d, J = benzoyl]amino]pyridine- Retention time 7.9 Hz, 1H), 7.21-7.12(m, 3H), 7.01- 2-carboxamide (Method B): 6.93 (m, 1H), 6.74 (s, 1H),3.96 (t, J = 7.8 0.83 minutes. Hz, 1H), 3.87 (td, J = 8.2, 4.8 Hz, 1H),3.75 (s, 4H), 3.53 (m, 1H), 3.44-3.29 (m, 1H), 2.28 (ddt, J = 12.6, 7.8,3.9 Hz, 1H), 1.83 (dq, J = 12.2, 7.7 Hz, 1H).

Example 2105-[[5-fluoro-7-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2,3-dihydro-1,4-benzodioxine-6-carbonyl]amino]pyridine-2-carboxamide(1034)

Step 1: 7-bromo-5-fluoro-2,3-dihydro-1,4-benzodioxine

To a mixture of 5-bromo-3-fluoro-benzene-1,2-diol (50 mg, 0.24 mmol) andK₂CO₃ (100 mg, 0.724 mmol) in DMF (0.75 mL) was added 1,2-dibromoethane(228 mg, 0.105 mL, 1.21 mmol). The reaction mixture was heated at 80° C.for 4 hours, then cooled to RT and stirred overnight. The reactionmixture was partitioned between water and ethyl acetate. Layers wereseparated and the aqueous phase was extracted with ethyl acetate (2×).The combined organic layers were concentrated under reduced pressure.Purification of the resulting residue via silica gel chromatography(ethyl acetate/hexanes gradient) provided7-bromo-5-fluoro-2,3-dihydro-1,4-benzodioxine (36 mg, 63%) as a whitesolid. Retention time (Method V): 2.91 minutes. ¹H NMR (250 MHz, CDCl₃)δ 6.92-6.78 (m, 2H), 4.29 (s, 4H) ppm.

Step 2: 7-bromo-5-fluoro-2,3-dihydro-1,4-benzodioxine-6-carboxylic acid

Lithium diisopropylamide (5.6 mL of 2 M, 11.2 mmol) was added to asolution of 7-bromo-5-fluoro-2,3-dihydro-1,4-benzodioxine (2.25 g, 9.27mmol) in anhydrous THF (90 mL) at −78° C. and stirred at thistemperature for 2 hours. The reaction mixture was transferred viacannula to dry ice and the slurry was allowed to come to RT over 48hours. The solvent was evaporated in vacuo. The resulting solid wasdissolved in 200 mL of 1 M NaOH solution and extracted once with 200 mLof ether. The aqueous layer was acidified to pH=1 using concentrated HCland extracted with ethyl acetate (2×200 mL). The combined organic layerswere washed with water (100 mL), brine (100 mL), dried over Na₂SO₄,filtered, and concentrated in vacuo to provide7-bromo-5-fluoro-2,3-dihydro-1,4-benzodioxine-6-carboxylic acid (2.3 g,86%) as a white solid. ESI-MS m/z calc. 275.94, found 276.9 (M+1)⁺;Retention time (Method W): 1.5 minutes. ¹H NMR (500 MHz, DMSO-d6) δ 7.10(d, J=2.0 Hz, 1H), 4.35 (s, 4H) ppm.

Step 3:5-fluoro-7-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2,3-dihydro-1,4-benzodioxine-6-carboxylicacid

To a pressure flask was added7-bromo-5-fluoro-2,3-dihydro-1,4-benzodioxine-6-carboxylic acid (1.03 g,3.72 mmol), 2-methoxy-4-(trifluoromethoxy)phenol (811 mg, 3.91 mmol),Cs₂CO₃ (1.27 g, 3.90 mmol) and toluene (10 mL). The reaction mixture wasbubbled with nitrogen for 10 minutes, then copper (I) iodide (164 mg,0.861 mmol) added. The flask was flushed with nitrogen, capped, andheated at 100° C. with vigorous stirring for 6 hours. Additional2-methoxy-4-(trifluoromethoxy)phenol (811 mg, 3.90 mmol), Cs₂CO₃ (1.27g, 3.90 mmol), copper (I) iodide (164 mg, 0.861 mmol) and toluene (6 mL)were added and the reaction was stirred at 100° C. for 3 hours. Themixture was allowed to cool, and then diluted with ethyl acetate andwater, and the aqueous layer acidified with 1 M HCl. The two layers wereseparated. The aqueous layer was extracted with ethyl acetate (3×). Thecombined organic layers were washed with water and brine, dried overNa₂SO₄, filtered through a plug of Celite and concentrated. Purificationby silica gel chromatography (ethyl acetate/hexanes gradient) provided5-fluoro-7-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2,3-dihydro-1,4-benzodioxine-6-carboxylicacid (455 mg, 30%). ESI-MS m/z calc. 404.05, found 405.11 (M+1)⁺;Retention time (Method C): 2.24 minutes. ¹H NMR (400 MHz, DMSO-d6) δ13.29 (s, 1H), 7.15 (d, J=2.7 Hz, 1H), 7.04-6.87 (m, 2H), 6.14 (s, 1H),4.30 (s, 4H), 3.81 (s, 3H) ppm.

Step 4:5-fluoro-7-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2,3-dihydro-1,4-benzodioxine-6-carbonylchloride

To a solution of5-fluoro-7-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2,3-dihydro-1,4-benzodioxine-6-carboxylicacid (103 mg, 0.25 mmol) and DMF (15 μL, 0.19 mmol) in dichloromethane(1 mL) at 0° C. was added oxalyl chloride (35 μL, 0.40 mmol) dropwiseunder nitrogen atmosphere. The ice bath was removed after 10 minutes andthe reaction was stirred at RT for 1 hour. The solvent was evaporatedunder reduced pressure to afford5-fluoro-7-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2,3-dihydro-1,4-benzodioxine-6-carbonylchloride (108 mg, 100%). The intermediate was used in the next stepwithout further purification.

Step 5:5-[[5-fluoro-7-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2,3-dihydro-1,4-benzodioxine-6-carbonyl]amino]pyridine-2-carboxamide(1034)

To 5-aminopyridine-2-carboxamide (65 mg, 0.47 mmol) in NMP (500 μL) andDIEA (153 mg, 206 μL, 1.18 mmol) at 0° C. was slowly added a solution of5-fluoro-7-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2,3-dihydro-1,4-benzodioxine-6-carbonylchloride (100 mg, 0.237 mmol) in NMP (1 mL). The mixture was stirred atRT for 1 hour. The reaction mixture was filtered and purified by HPLC(1-99% CH₃CN/5 mM HCl) to provide5-[[5-fluoro-7-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2,3-dihydro-1,4-benzodioxine-6-carbonyl]amino]pyridine-2-carboxamide(40 mg, 33%). ESI-MS m/z calc. 523.10, found 524.2 (M+1)⁺; Retentiontime (Method C): 2.18 minutes. ¹H NMR (400 MHz, DMSO-d6) δ 11.05 (s,1H), 8.82 (d, J=2.4 Hz, 1H), 8.21 (dd, J=8.6, 2.4 Hz, 1H), 8.12-7.90 (m,2H), 7.54 (s, 1H), 7.23-7.03 (m, 2H), 6.93 (d, J=9.3 Hz, 1H), 6.21 (s,1H), 4.33 (s, 4H), 3.74 (s, 3H) ppm.

The compounds set forth in Table 109 were prepared by methods analogousto the preparation of compound 1034.

TABLE 109 Additional Compounds Prepared by Methods Analogous to Example210 (compound 1034) Cmpd No. Compound Name LC/MS NMR (shifts in ppm)1035 4-[[5-fluoro-7-[2- ESI-MS m/z ¹H NMR (400 MHz, DMSO-d6) δ 11.16 (s,methoxy-4- calc. 523.10, 1H), 8.50 (d, J = 5.5 Hz, 1H), 8.27 (d, J =(trifluoromethoxy)phe- found 524.17 2.2 Hz, 1H), 8.10 (s, 1H), 7.96-7.75(m, noxy]-2,3-dihydro-1,4- (M + 1)+; 1H), 7.65 (d, J = 2.9 Hz, 1H),7.19-7.04 benzodioxine-6- Retention time (m, 2H), 6.93 (d, J = 8.9 Hz,1H), 6.19 (d, carbonyl]amino]pyridine- (Method C): J = 1.8 Hz, 1H), 4.33(s, 4H), 3.74 (s, 3H). 2-carboxamide 2.17 minutes.

Example 2114-[[6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-2,3-dihydro-1,4-benzodioxine-7-carbonyl]amino]pyridine-2-carboxamide(1036)

Step 1:6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-2,3-dihydro-1,4-benzodioxine-7-carboxylicacid

To a pressure flask was added6-bromo-2,3-dihydro-1,4-benzodioxine-7-carboxylic acid (2.0 g, 7.7mmol), 2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenol Example 202,Step 2) (1.70 g, 8.04 mmol), Cs₂CO₃ (2.62 g, 8.04 mmol) and toluene (15mL). The reaction mixture was bubbled with nitrogen for 10 minutes, thencopper (I) iodide (345 mg, 1.81 mmol) added. The flask was flushed withnitrogen, capped, and heated at 100° C. with vigorous stirring for 22hours. The mixture was allowed to cool to RT and then partitionedbetween ethyl acetate and water. The organic layer was washed with water(×2), brine, dried over Na₂SO₄, filtered through a plug of Celite andconcentrated. Purification via silica gel chromatography (ethylacetate/hexanes gradient) provided6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-2,3-dihydro-1,4-benzodioxine-7-carboxylicacid (449 mg, 15%). ESI-MS m/z calc. 389.08, found 390.2 (M+1)⁺;Retention time (Method C): 2.29 minutes. ¹H NMR (400 MHz, DMSO-d6) δ12.59 (s, 1H), 7.34 (s, 1H), 7.12 (d, J=2.8 Hz, 1H), 6.90-6.82 (m, 1H),6.76 (d, J=8.8 Hz, 1H), 6.36 (s, 1H), 4.33-4.22 (m, 4H) ppm.

Step 2:6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-2,3-dihydro-1,4-benzodioxine-7-carbonylchloride

To a solution of6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-2,3-dihydro-1,4-benzodioxine-7-carboxylicacid (440 mg, 1.13 mmol) and DMF (15 μL, 0.19 mmol) in dichloromethane(3.5 mL) at 0° C. was added oxalyl chloride (150 μL, 1.72 mmol) dropwiseunder nitrogen atmosphere. The ice bath was removed after 10 minutes andthe reaction was stirred at RT for 1 hour. The solvent was evaporatedunder reduced pressure to afford6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-2,3-dihydro-1,4-benzodioxine-7-carbonylchloride. The intermediate was used in the next step without furtherpurification.

Step 3:4-[[6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-2,3-dihydro-1,4-benzodioxine-7-carbonyl]amino]pyridine-2-carboxamide(1036)

To a solution of 4-aminopyridine-2-carboxamide (20 mg, 0.15 mmol) andDIEA (47 mg, 64 μL, 0.37 mmol) in NMP (500 μL) at 0° C. was slowly addeda solution of6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-2,3-dihydro-1,4-benzodioxine-7-carbonylchloride (50 mg, 0.12 mmol) in NMP (200 μL). The reaction was allowed towarm to RT and stirred for 1 hour. The crude product was filtered andpurified by HPLC (1-99% CH₃CN/5 mM HCl) to provide4-[[6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-2,3-dihydro-1,4-benzodioxine-7-carbonyl]amino]pyridine-2-carboxamide(11.7 mg, 19%). ESI-MS m/z calc. 508.13, found 508.95 (M+1)⁺; Retentiontime (Method B): 1.72 minutes. ¹H NMR (400 MHz, DMSO-d6) δ 10.63 (s,1H), 8.48 (d, J=5.5 Hz, 1H), 8.26 (d, J=2.6 Hz, 1H), 8.10 (s, 1H), 7.83(dd, J=5.6, 2.5 Hz, 1H), 7.64 (s, 1H), 7.25 (d, J=2.2 Hz, 1H), 7.14-7.03(m, 2H), 6.93 (d, J=8.8 Hz, 1H), 6.41 (d, J=2.1 Hz, 1H), 4.28 (d, J=8.0Hz, 4H) ppm.

The compounds set forth in Table 110 were prepared by methods analogousto the preparation of compound 1036

TABLE 110 Additional Compounds Prepared by Methods Analogous to Example211 Cmpd No. Compound Name LC/MS NMR (shifts in ppm) 1037 5-[[6-[2-ESI-MS m/z ¹H NMR (400 MHz, DMSO-d₆) δ (trideuteriomethoxy)-4- calc.508.13, 10.53 (s, 1H), 8.83 (d, J = 2.6 Hz, (trifluoromethoxy)phe- found509.1 1H), 8.25-8.12 (m, 1H), 7.99 (d, noxy]-2,3-dihydro-1,4- (M + 1)+;J = 11.0 Hz, 2H), 7.53 (s, 1H), 7.25 benzodioxine-7- Retention time (t,J = 2.0 Hz, 1H), 7.11 (d, J = 2.6 carbonyl]amino]pyridine- (Method C):Hz, 1H), 7.06 (d, J = 8.8 Hz, 1H), 2-carboxamide 2.51 minutes. 6.93 (d,J = 8.9 Hz, 1H), 6.42 (d, J = 2.0 Hz, 1H), 4.28 (d, J = 6.8 Hz, 4H).

Example 2124-[[4-(3-fluorocyclobut-2-en-1-yl)oxy-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-benzoyl]amino]pyridine-2-carboxamide(1038)

Step 1: 2,6-dichloro-4-(3,3-difluorocyclobutoxy)benzonitrile

2,6-Dichloro-4-fluoro-benzonitrile (940 mg, 4.95 mmol),3,3-difluorocyclobutanol (625 mg, 5.78 mmol) and NaH (283 mg of 60% w/w,7.08 mmol) were combined in THF (8 mL) and heated at 60° C. undernitrogen for 2 hours. The mixture was allowed to cool, diluted withethyl acetate and washed with 2 M NaOH. The organic layer was separated,dried over MgSO₄ and concentrated to provide2,6-dichloro-4-(3,3-difluorocyclobutoxy)benzonitrile (1.485 g, 108%). ¹HNMR (500 MHz, Chloroform-d) δ 6.88 (s, 2H), 4.79-4.62 (m, 1H), 3.25-3.10(m, 2H), 2.91-2.71 (m, 2H) ppm. The crude material was taken on to thenext step.

Step 2:2-chloro-4-(3,3-difluorocyclobutoxy)-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzonitrile

2-Methoxy-4-(trifluoromethoxy)phenol (1.288 g, 6.188 mmol),2,6-dichloro-4-(3,3-difluorocyclobutoxy)benzonitrile (1.485 g, 5.340mmol) and Cs₂CO₃ (2.162 g, 6.636 mmol) were combined in DMF (8 mL) andheated at 95° C. for 16 hours. The reaction was allowed to cool then waspartitioned between ethyl acetate and brine. The organic layer wasseparated, dried over MgSO₄ and concentrated. Silica gel chromatography(0-20% ethyl acetate/heptane) provided2-chloro-4-(3,3-difluorocyclobutoxy)-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzonitrile(1.794 g, 75%). ¹H NMR (500 MHz, DMSO-d6) δ 8.70 (dd, J=8.6, 1.9 Hz,1H), 8.50-8.40 (m, 2H), 8.13 (d, J=2.2 Hz, 1H), 7.54 (d, J=2.3 Hz, 1H),6.21-6.08 (m, 1H), 5.36 (s, 3H), 4.58 (dddd, J=15.4, 13.9, 8.0, 4.4 Hz,2H), 4.32-4.14 (m, 2H) ppm.

Step 3:4-(3,3-difluorocyclobutoxy)-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-benzonitrile

Methylboronic acid (651 mg, 10.9 mmol), Cs₂CO₃ (2.16 g, 6.63 mmol) and2-chloro-4-(3,3-difluorocyclobutoxy)-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzonitrile(971 mg, 2.16 mmol) were degassed in dioxane (15 mL) then treated withPd(dppf)Cl₂ (79 mg, 0.11 mmol). The mixture was heated at 100° C. undernitrogen for 17 hours, and then at 110° C. for 4 hours. The mixture wasallowed to cool then diluted with ethyl acetate and washed withsaturated aqueous NaHCO₃. The organic layer was separated, dried overMgSO₄ and concentrated. Silica gel chromatography (0-10% ethylacetate/heptane) provided4-(3,3-difluorocyclobutoxy)-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-benzonitrile(275 mg, 30%). ESI-MS m/z calc. 429.10, found 430.6 (M+1)⁺; Retentiontime (Method F): 1.05 minutes. ¹H NMR (500 MHz, Chloroform-d) δ 7.11 (d,J=8.5 Hz, 1H), 6.93-6.88 (m, 2H), 6.39-6.33 (m, 1H), 5.90 (d, J=2.2 Hz,1H), 4.56 (dtq, J=8.7, 5.1, 1.9 Hz, 1H), 3.82 (s, 3H), 3.01 (ddt,J=15.3, 12.1, 6.8 Hz, 2H), 2.79-2.61 (m, 2H), 2.54 (s, 3H) ppm.

Step 4:4-(3-fluorocyclobut-2-en-1-yl)oxy-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-benzamide

4-(3,3-Difluorocyclobutoxy)-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-benzonitrile(275 mg, 0.641 mmol) in ethanol (3 mL) and NaOH (3 mL of 2 M, 6 mmol)were heated at 150° C. in the microwave for 1 hour. The mixture wasdiluted with ethyl acetate and washed with saturated aqueous NaHCO₃. Theorganic layer was separated, dried over MgSO₄ and concentrated toprovide4-(3-fluorocyclobut-2-en-1-yl)oxy-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-benzamide(254 mg, 93%). ESI-MS m/z calc. 427.10, found 428.6 (M+1)⁺; Retentiontime (Method F): 0.92 minutes.

Step 5:4-[[4-(3-fluorocyclobut-2-en-1-yl)oxy-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-benzoyl]amino]pyridine-2-carboxamide(1038)

Methyl 4-bromopyridine-2-carboxylate (159 mg, 0.737 mmol), Xantphos (74mg, 0.13 mmol), cesium carbonate (467 mg, 1.43 mmol), Pd(OAc)₂ (14 mg,0.062 mmol) and4-(3-fluorocyclobut-2-en-1-yl)oxy-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-benzamide(258 mg, 0.604 mmol) were combined in dioxane (8 mL). The mixture wasdegassed then heated at 100° C. under nitrogen for 1 hour. The mixturewas allowed to cool then diluted with ethyl acetate and washed withsaturated aqueous NaHCO₃. The organic layer was dried over MgSO₄,filtered and concentrated. Silica gel chromatography (0-80% ethylacetate/heptane gradient) provided the intermediate4-(4-((3-fluorocyclobut-2-en-1-yl)oxy)-2-(2-methoxy-4-(trifluoromethoxy)phenoxy)-6-methylbenzamido)picolinamide.The intermediate was dissolved in a solution of ammonia in methanol (4.5mL of 7 M, 31.5 mmol) and stirred at room temperature for 14 hours. Thereaction mixture was concentrated and purified by HPLC (CH₃CN/water withammonia modifier gradient) to provide4-[[4-(3-fluorocyclobut-2-en-1-yl)oxy-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-6-methyl-benzoyl]amino]pyridine-2-carboxamide(8.3 mg, 2%). ESI-MS m/z calc. 547.14, found 548.6 (M+1)⁺; Retentiontime (Method E): 3.43 minutes. ¹H NMR (400 MHz, DMSO-d6) δ 11.02 (s,1H), 8.50 (d, J=5.5 Hz, 1H), 8.34 (d, J=2.4 Hz, 1H), 8.07 (d, J=2.9 Hz,1H), 7.83 (dd, J=5.5, 2.2 Hz, 1H), 7.62 (d, J=2.9 Hz, 1H), 7.24-7.12 (m,3H), 6.98 (ddd, J=8.8, 2.7, 1.2 Hz, 1H), 6.92 (dd, J=2.3, 0.7 Hz, 1H),6.26 (d, J=2.3 Hz, 1H), 6.01 (dd, J=27.0, 12.1 Hz, 1H), 4.71-4.65 (m,1H), 4.59 (dd, J=41.1, 3.0 Hz, 1H), 3.76 (s, 3H), 2.34 (s, 3H) ppm.

Example 2134-[[3-methyl-2-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(1039)

Step 1: 3-bromo-2-fluoro-5-(trifluoromethyl)benzoic acid

n-BuLi (45 mL of 2.5 M, 112.50 mmol) in hexane was added to a solutionof diisopropylamine (11.6 g, 16.0 mL, 114 mmol) in tetrahydrofuran (100mL) at −30° C. The mixture was stirred at −30° C. for 45 minutes, thencooled to −78° C. and a solution of2-bromo-1-fluoro-4-(trifluoromethyl)benzene (25.0 g, 103 mmol) intetrahydrofuran (25 mL) was slowly added. The reaction mixture wasstirred at −78° C. for 3 hours. Solid CO₂ (40-50 g) were addedportionwise. The cold bath was removed and the reaction allowed to warmto RT. The solvents were evaporated and the residue was diluted with 1 MNaOH (100 mL) and water (50 mL). The aqueous layer was washed withdichloromethane (2×) then acidified with 3 M HCl until pH<2 was reached.The aqueous layer was extracted with dichloromethane (3×) and thecombined organics dried over Na₂SO₄, filtered and concentrated toprovide 18.1 g of beige solid. The solid was triturated in heptane (125mL) to provide 3-bromo-2-fluoro-5-(trifluoromethyl)benzoic acid (8.9 g)as a beige solid. The filtrate was evaporated and the residue wastriturated with minimal heptane to provide additional3-bromo-2-fluoro-5-(trifluoromethyl)benzoic acid (3.03 g). Both crops ofsolid were combined in dichloromethane (300 mL). The organic layer waswashed with 1 M HCl, dried over Na₂SO₄, filtered and concentrated toprovide 3-bromo-2-fluoro-5-(trifluoromethyl)benzoic acid (9.86 g, 29%)as a light brown solid. ¹H NMR (300 MHz, DMSO-d6) δ 8.39 (dd, J=5.6, 2.2Hz, 1H), 8.10 (dd, J=5.9, 2.2 Hz, 1H) ppm. ¹⁹F NMR (282 MHz, DMSO-d6) δ−60.90 (s, 3F), −98.40-98.51 (m, 1F) ppm.

Step 2:3-bromo-2-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)benzoicacid

Cs₂CO₃ (2.55 g, 7.83 mmol) was added to a solution of2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenol (prepared in Example202, Step 2, 674 mg, 3.19 mmol) in NMP (10 mL). The mixture was stirredfor 10 minutes then treated with3-bromo-2-fluoro-5-(trifluoromethyl)benzoic acid (900 mg, 2.76 mmol) andheated at 120° C. for 18 hours. The reaction was cooled to RT anddiluted with 1 M HCl. The aqueous layer was extracted with ethyl acetate(3×). The combined organic layers were washed with water and brine,dried over Na₂SO₄, filtered and concentrated in vacuo to provide3-bromo-2-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)benzoicacid (2.32 g, 56%). ESI-MS m/z calc. 476.97, found 475.9 (M−1)+;Retention time (Method E): 2.2 minutes.

Step 3:3-methyl-2-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)benzoicacid

A mixture of3-bromo-2-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)benzoicacid (4.00 g, 8.37 mmol), Cs₂CO₃ (6.95 g, 21.3 mmol) and trimethylboroxine (2.2 g, 2.4 mL, 17 mmol) in dioxane (35 mL) and water (6 mL)was degassed with nitrogen for 5 minutes. Pd(dppf)Cl₂.DCM (334 mg, 0.409mmol) was added and the reaction mixture was purged with nitrogen (3×).The reaction mixture was stirred at 100° C. for 17 hours, then cooled toRT and partitioned between 1 M HCl and dichloromethane. The organiclayer was separated and the aqueous layer extracted with additionaldichloromethane (2×). The combined organic layers were dried overNa₂SO₄, filtered and concentrated in vacuo. Silica gel chromatography(0-5% methanol/dichloromethane gradient) provided 2.81 g of an off-whitesolid. The solid was triturated in 5:1 heptane/dichloromethane (20 mL)to provide3-methyl-2-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)benzoicacid (2.51 g, 72%). ESI-MS m/z calc. 413.08, found 412.2 (M−1)⁻;Retention time (Method M): 3.33 minutes. ¹H NMR (300 MHz, DMSO-d6) δ13.30 (br s., 1H), 7.95 (s, 2H), 7.12 (d, J=2.6 Hz, 1H), 6.75 (dd,J=8.8, 1.5 Hz, 1H), 6.40 (d, J=8.8 Hz, 1H), 2.12 (s, 3H) ppm. ¹⁹F NMR(282 MHz, DMSO-d6) δ −57.13 (s, 3F), −60.95 (s, 3F) ppm.

Step 4:4-[[3-methyl-2-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(1039)

To a solution of3-methyl-2-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)benzoicacid (100 mg, 0.242 mmol) and DMF (1 μL, 0.01 mmol) in dichloromethane(1 mL) was slowly added oxalyl chloride (175 μL, 2.01 mmol). Thereaction mixture was allowed to stir at RT for 1 hour and thenconcentrated in vacuo. The resulting residue was taken up indichloromethane (1 mL) and added dropwise to a stirring solution of4-aminopyridine-2-carboxamide (40 mg, 0.29 mmol) and DIEA (250 μL, 1.44mmol) in dichloromethane (1 mL). The reaction was stirred for 16 hoursthen purified by HPLC (10-75% CH₃CN/5 mM HCl) to provide4-[[3-methyl-2-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(32 mg, 25%). ESI-MS m/z calc. 532.13, found 533.2 (M+1)⁺; Retentiontime (Method B): 1.86 minutes. ¹H NMR (400 MHz, DMSO-d₆) δ 11.00 (s,1H), 8.45 (d, J=5.5 Hz, 1H), 8.15 (d, J=2.2 Hz, 1H), 8.07 (d, J=2.8 Hz,1H), 8.03-7.92 (m, 1H), 7.87 (d, J=2.4 Hz, 1H), 7.74-7.52 (m, 2H), 6.97(d, J=2.8 Hz, 1H), 6.83-6.68 (m, 1H), 6.59 (d, J=8.9 Hz, 1H), 2.24 (s,3H) ppm.

Example 2144-[[2-hydroxy-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(383)

Step 1:2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoylchloride

Thionyl chloride (13.2 mL, 181 mmol) was added to a solution of2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoicacid (50.0 g, 121 mmol, See Example 5, Step 2) in toluene (375 mL) undernitrogen. The mixture was heated at 70° C. for 14 hours. The reactionwas cooled to 0° C. then washed with ice water (2×375 mL) and brine. Theorganic layer was dried over MgSO₄, filtered and concentrated to provide2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoylchloride.

Step 2: methyl4-[[2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxylate

A solution of2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoylchloride (6.35 g, 14.7 mmol) in dichloromethane (16 mL) was added to asuspension of methyl 4-aminopyridine-2-carboxylate (2.69 g, 17.7 mmol)in 2-MeTHF (63.5 mL) and DIEA (6.4 mL, 37 mmol) at 19.2° C. over 4minutes (reaction exotherm raised the solution temperature to 27.8° C.).The mixture was stirred for 23 hours, then washed sequentially with 2:1water/brine (100 mL), a solution of 2:1 brine/1 M aqueous HCl (2×100mL), a solution of 1:1 brine/saturated sodium bicarbonate (100 mL) andbrine. The organic phase was dried over MgSO₄, filtered andconcentrated. Purification by silica gel chromatography (10-70% ethylacetate/hexanes) provided methyl4-[[2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxylate(6.6 g, 81%). ESI-MS m/z calc. 548.08, found 549.2 (M+1)⁺; LC/MSretention time (Method B): 1.86 minutes. ¹H NMR (400 MHz, DMSO-d₆) δ11.51 (s, 1H), 8.64 (d, J=5.5 Hz, 1H), 8.39 (d, J=2.1 Hz, 1H), 7.91-7.75(m, 2H), 7.37 (d, J=8.8 Hz, 1H), 7.26 (d, J=2.7 Hz, 1H), 7.10-6.99 (m,1H), 6.69 (d, J=8.9 Hz, 1H), 3.89 (s, 3H), 3.79 (s, 3H) ppm.

Step 3: methyl4-[[2-hydroxy-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxylate

A mixture of methyl4-[[2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxylate(50 mg, 0.091 mmol), hydroxylamine hydrochloride (32 mg, 0.46 mmol) andK2CO₃ (63 mg, 0.46 mmol) in DMF (500 μL) was stirred at room temperaturefor 24 hours and then at 75° C. for 18 hours. In a separate reactionvessel, a mixture of methyl4-[[2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxylate(50 mg, 0.091 mmol), N-methylhydroxylamine hydrochloride (38 mg, 0.46mmol) and K2CO₃ (63 mg, 0.46 mmol) in DMF (500 μL) was stirred at roomtemperature for 24 hours and then at 75° C. for 18 hours. Both reactionsresulted in predominant formation of methyl4-[[2-hydroxy-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxylate.The two reaction mixtures were combined, partitioned between ethylacetate and 1 M aqueous citric acid and the layers separated. Theorganic layer was concentrated and purified by silica gel chromatography(0-100% ethyl acetate/hexanes) to provide methyl4-[[2-hydroxy-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxylate(22 mg, 22%). ESI-MS m/z calc. 546.09, found 547.0 (M+1)⁺; LC/MSretention time (Method E): 2.92 minutes. ¹H NMR (400 MHz, DMSO-d₆) δ11.17 (s, 1H), 10.87 (s, 1H), 8.59 (d, J=5.5 Hz, 1H), 8.44 (d, J=2.1 Hz,1H), 7.83 (dd, J=5.6, 2.1 Hz, 1H), 7.56 (d, J=8.9 Hz, 1H), 7.28 (d,J=9.0 Hz, 1H), 7.20 (d, J=2.7 Hz, 1H), 7.01 (ddd, J=8.8, 2.9, 1.4 Hz,1H), 6.22 (d, J=8.8 Hz, 1H), 3.88 (s, 3H), 3.77 (s, 3H) ppm.

Step 4:4-[[2-hydroxy-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide

Methyl4-[[2-hydroxy-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxylate(9 mg, 0.02 mmol) was dissolved in acetonitrile and treated with aqueous28% NH₄OH (˜1 mL). The solution was left standing for approximately 48hours and was then concentrated and purified by reverse phase HPLC(acetonitrile/5 mM HCl gradient) to provide4-[[2-hydroxy-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide(6 mg, 70%). ESI-MS m z calc. 531.09, found 532.0 (M+1)⁺; LC/MSretention time (Method C): 2.84 minutes. ¹H NMR (400 MHz, DMSO-d₆) δ11.20-10.99 (m, 1H), 10.90 (s, 1H), 8.51 (d, J=5.5 Hz, 1H), 8.37 (d,J=2.1 Hz, 1H), 8.08 (d, J=2.9 Hz, 1H), 7.84 (dd, J=5.5, 2.1 Hz, 1H),7.63 (d, J=2.9 Hz, 1H), 7.55 (d, J=8.9 Hz, 1H), 7.30 (d, J=8.9 Hz, 1H),7.21 (d, J=2.7 Hz, 1H), 7.12-6.92 (m, 1H), 6.22 (d, J=8.8 Hz, 1H), 3.78(s, 3H) ppm.

Example 215 Additional Compounds of the Invention

The compounds set forth in Table 111 were prepared by the general methodset forth in Scheme 2. Alkylation of 5-bromo-3-fluorobenzene-1,2-diolwith 3-bromo-2-methylprop-1-ene, followed by ring closure afforded apair of isomeric substituted dihydrobenzodioxines. After separation ofthe isomers, carbonylation, Ullmann coupling, and amide formationafforded compounds 1040 and 1041. As an alternative to the method shownin Scheme 2, the isomeric dihydrobenzodioxines can be separated afterthe carbonylation step.

TABLE 111 Additional Compounds Prepared By the Methods of Scheme 2 CmpdNo. Compound Name LC/MS NMR (shifts in ppm) 10404-(5-fluoro-7-(3-fluoro- ESI-MS m/z ¹H NMR (400 MHz, DMSO-d₆) δ 11.23(s, 2-methoxy-4- found 570.2 1H), 8.50 (d, J = 5.5 Hz, 1H), 8.27 (d, J =(trifluoromethoxy)phe- (M + 1); 2.1 Hz, 1H), 8.08 (d, J = 2.8 Hz, 1H),7.77 noxy)-2,2-dimethyl-2,3- Retention time: (dd, J = 5.5, 2.2 Hz, 1H),7.64 (d, J = 2.7 dihydrobenzo[b][1,4]dioxine- 2.56 minutes. Hz, 1H),7.27 (t, J = 8.7 Hz, 1H), 6.90 (dd, 6-carboxamido)picolinamide J = 9.3,2.1 Hz, 1H), 6.44 (d, J = 1.8 Hz, 1H), 4.06 (s, 2H), 3.83 (s, 3H), 1.33(s, 6H). 1041 4-(5-fluoro-7-(3-fluoro- ESI-MS m/z ¹H NMR (400 MHz,DMSO-d₆) δ 11.22 (s, 2-methoxy-4- found 570.2 1H), 8.49 (d, J = 5.5 Hz,1H), 8.26 (d, J = (trifluoromethoxy)phe- (M + 1); 2.2 Hz, 1H), 8.07 (d,J = 2.9 Hz, 1H), 7.76 noxy)-3,3-dimethyl-2,3- Retention time: (dd, J =5.5, 2.2 Hz, 1H), 7.63 (d, J = 2.8 dihydrobenzo[b][1,4]dioxine- 2.48minutes. Hz, 1H), 7.35-7.18 (m, 1H), 6.89 (dd, J =6-carboxamido)picolinamide 9.4, 2.1 Hz, 1H), 6.59 (d, J = 1.8 Hz, 1H),4.07 (s, 2H), 3.83 (s, 3H), 1.35 (s, 6H).

Example 216 E-VIPR Assay for Detecting and Measuring Na_(V) InhibitionProperties

Sodium ion channels are voltage-dependent proteins that can be activatedby inducing membrane voltage changes by applying electric fields. Theelectrical stimulation instrument and methods of use, referred to asE-VIPR, are described in International Publication No. WO 2002/008748 A3and C.-J. Huang et al. Characterization of voltage-gated sodium channelblockers by electrical stimulation and fluorescence detection ofmembrane potential, 24 Nature Biotech. 439-46 (2006), both of which areincorporated by reference in their entirety. The instrument comprises amicrotiter plate handler, an optical system for exciting the coumarindye while simultaneously recording the coumarin and oxonol emissions, awaveform generator, a current- or voltage-controlled amplifier, andparallel electrode pairs that are inserted into assay plate wells. Underintegrated computer control, this instrument passes user-programmedelectrical stimulus protocols to cells within the wells of themicrotiter plate.

16-20 hours prior to running the assay on E-VIPR, HEK cells expressing atruncated form of human Na_(V) 1.8 with full channel activity wereseeded into microtiter 384-well plates, pre-coated with matrigel, at adensity of 25,000 cells per well. 2.5-5% KIR2.1 Bacmam virus was addedto the final cell suspension before seeding into cell plates. HEK cellswere grown in Dulbecco's Modified Eagle's Medium (DMEM) supplementedwith 10% FBS (Fetal Bovine Serum, qualified; Sigma #F4135), 1% NEAA(Non-Essential Amino Acids, Gibco #11140), 1% HEPES (Gibco #15630), 1%Pen-Strep (Penicillin-Streptomycin; Gibco #15140) and 5 μg/mlBlasticidin (Gibco #R210-01). Cells were expanded in vented cap cellculture flasks, with 90-95% humidity and 5% CO₂.

Reagents and Stock Solutions:

100 mg/mL Pluronic F-127 (Sigma #P2443), in dry DMSO

Compound Plates: Coming 384-well Polypropylene Round Bottom #3656

Cell Plates: 384-well tissue culture treated plates (Greiner #781091-1B)

2.5-5% KIR 2.1 Bacmam virus (produced in-house), prepared as describedin Section 3.3 of J. A. Fornwald et al., Gene Expression in MammalianCells Using BacMam, a Modified Baculovirus System, 1350 Methods inMolecular Biology 95-116 (2016), the entire contents of which areincorporated by reference. The concentration used can be dependent onviral titer of each batch.

5 mM DiSBAC₆(3), a voltage sensitive oxonol acceptor (CAS number169211-44-3;5-[3-(1,3-dihexylhexahydro-4,6-dioxo-2-thioxo-5-pyrimidinyl)-2-propen-1-ylidene]-1,3-dihexyldihydro-2-thioxo-4,6(1H,5H)-pyrimidinedione),in dry DMSO. The preparation of DiSBAC₆(3) is analogous to that ofDiSBAC₄(3) as described in Voltage Sensing by Fluorescence ResonanceEnergy Transfer in Single Cells, Gonzalez, J. E. and Tsien, R. Y. (1995)Biophys. J 69, 1272-1280.

5 mM CC2-DMPE, a commercially available membrane-bound coumarinphospholipid FRET donor (ThermoFisher Scientific catalog number K1017,CAS number 393782-57-5; tetradecanoic acid,1,1′-[(1R)-1-[8-(6-chloro-7-hydroxy-2-oxo-2H-1-benzopyran-3-yl)-3-hydroxy-3-oxido-8-oxo-2,4-dioxa-7-aza-3-phosphaoct-1-yl]-1,2-ethanediyl]ester)was prepared in dry DMSO. See also, Improved indicators of cell membranepotential that use fluorescence resonance energy transfer, Gonzalez, J.E. and Tsien, R. Y. (1997) Chem. Biol. 4, 269-277.

Voltage Assay Background Suppression Compound (VABSC-1) is prepared inH₂O (89-363 mM, range used to maintain solubility)

Human Serum (HS, Millipore #S1P1-01KL, or Sigma SLBR5469V and SLBR5470Vas a 50%/50% mixture, for 25% assay final concentration)

Bath1 Buffer:

-   -   Sodium Chloride 160 mM (9.35 g/L), Potassium Chloride, 4.5 mM        (0.335 g/L), Glucose 10 mM (1.8 g/L), Magnesium Chloride        (Anhydrous) 1 mM (0.095 g/L), Calcium Chloride 2 mM (0.222 g/L),        HEPES 10 mM (2.38 g/L) in water.

Na/TMA Cl Bath1 Buffer:

-   -   Sodium Chloride 96 mM (5.61 g/L), Potassium Chloride 4.5 mM        (0.335 g/L), Tetramethylammonium (TMA)-Cl 64 mM (7.01 g/L),        Glucose 10 mM (1.8 g/L), Magnesium Chloride (Anhydrous) 1 mM        (0.095 g/L), Calcium Chloride 2 mM (0.222 g/L) HEPES 10 mM (2.38        g/L) in water.

Hexyl Dye Solution (2× Concentration):

-   -   Bath1 Buffer containing 0.5% β-cyclodextrin (made fresh prior to        each use, Sigma #C4767), 8 μM CC2-DMPE and 2 μM DiSBAC₆(3). The        solution was made by adding 10% Pluronic F127 stock equal to        combined volumes of CC2-DMPE and DiSBAC₆(3). The order of        preparation was first mix Pluronic and CC2-DMPE, then add        DiSBAC₆(3), then while vortexing add Bath1/β-Cyclodextrin.

Compound Loading Buffer (2× concentration): Na/TMA Cl Bath1 Buffercontaining HS (omitted in experiments run in the absence of human serum(HS)) 50%, VABSC-1 1 mM, BSA 0.2 mg/ml (in Bath-1), KCl 9 mM, DMSO0.75%.

Assay Protocol (7 Key Steps):

1) To reach the final concentration in each well, 400 nL of eachcompound was pre-spotted (in neat DMSO) into polypropylene compoundplates at 250× desired final concentration from an intermediate stockconcentration of 0.075 mM, in an 11 point dose response, 3-folddilution, resulting in a top dose of 300 nM final concentration in thecell plate. Vehicle control (neat DMSO), and positive control (anestablished Na_(V)1.8 inhibitor, 25 μM final in assay in DMSO) wereadded manually to the outermost columns of each plate respectively. Thecompound plate was backfilled with 45 μL per well of Compound LoadingBuffer resulting in a 250 fold dilution of compound following a 1:1transfer of compound into the cell plate (see Step 6). Final DMSOconcentration for all wells in the assay was 0.625% (0.75% DMSO wassupplemented to the Compound Loading Buffer for a final DMSOconcentration of 0.625%). This assay dilution protocol was adjusted toenable a higher dose range to be tested in the presence of HS or if thefinal assay volume was altered.

2) Hexyl Dye Solution was prepared.

3) Cell plates were prepared. On the day of the assay, the media wasaspirated, and the cells were washed three times with 80 μL of Bath-1buffer, maintaining 25 μL residual volume in each well.

4) 25 μL per well of Hexyl Dye Solution was dispensed into the cellplates. The cells were incubated for 20 minutes at room temperature orambient conditions in darkness.

5) 45 μL per well of Compound Loading Buffer was dispensed into compoundplates.

6) The cell plates were washed three times with 80 μL per well of Bath-1Buffer, leaving 25 L of residual volume. Then 25 μL per well fromcompound plate was transferred to each cell plate. The mixture wasincubated for 30 minutes at room temperature/ambient conditions.

7) The cell plate containing compound was read on E-VIPR using thecurrent-controlled amplifier to deliver stimulation wave pulses using asymmetrical biphasic waveform. The user-programmed electrical stimulusprotocols were 1.25-4 Amps and 4-6 millisecond pulse width (dependent onelectrode composition) were delivered at 10 Hz for 10 seconds. Apre-stimulus recording was performed for each well for 0.5 seconds toobtain the un-stimulated intensities baseline. The stimulatory waveformwas followed by 0.5 seconds of post-stimulation recording to examine therelaxation to the resting state. All E-VIPR responses were measured at200 Hz acquisition rate.

Data Analysis:

Data were analyzed and reported as normalized ratios of emissionintensities measured in the 460 nm and 580 nm channels. The response asa function of time was reported as the ratios obtained using thefollowing formula:

${R(t)} = \frac{\left( {intensity}_{460{nm}} \right)}{\left( {intensity}_{580{nm}} \right)}$

The data were further reduced by calculating the initial (Ri) and final(R_(f)) ratios. These were the average ratio values during part or allof the pre-stimulation period and during sample points during thestimulation period. The fluorescence ratio (R_(f)/Ri) was thencalculated and reported as a function of time.

Control responses were obtained by performing assays in the presence ofthe positive control, and in the absence of pharmacological agents (DMSOvehicle negative control). Responses to the negative (N) and positive(P) controls were calculated as above. The compound antagonist %activity A was then defined as:

$A = {\frac{X - N}{P - N} \times 100}$

where X is the ratio response of the test compound. Using this analysisprotocol, dose response curves were plotted and IC₅₀ values weregenerated for various compounds of the present invention as reportedbelow in Table 112.

TABLE 112 IC₅₀ Values of Compounds of the Invention in E-VIPR Assay Cmpd# IC₅₀ (μM)  1 0.39  2 0.45  3 1.4  4 0.65  5 1.2  6 1.7  7 0.66  8 0.51 9 1.3  10 0.65  11 1.4  12 2.1  13 >3  14 >3  15 >3  16 >3  17 >3  180.019  19 0.057  20 0.048  21 1  22 0.54  23 0.15  24 0.2  25 0.16  261.3  27 0.17  28 0.024  29 0.045  30 0.043  31 0.009  32 0.2  33 0.017 34 0.12  35 0.51  36 0.18  37 0.026  38 0.043  39 >3  40 >3  41 0.01 42 0.008  43 0.013  44 0.022  45 >3  46 >3  47 1.4  48 0.05  49 0.042 50 0.033  51 0.2  52 0.17  53 0.11  54 0.51  55 0.42  56 0.048  57 0.35 58 0.15  59 0.1  60 0.52  61 0.49  62 0.44  63 1.8  64 0.063  65 0.036 66 0.016  67 0.11  68 0.29  69 >3  70 >3  71  72 0.56  73 1.5  74 1.2 75 1.75  76  77 >3  78 >3  79 >3  80 >3  81 >3  82 >3  83 0.16  840.625  85 0.18  86 1  87 1.5  88 0.039  89 0.036  90 0.21  91 0.44  920.063  93 0.013  94 0.039  95 0.14  96 0.013  97 0.014  98 0.023  990.38 100 0.63 101 0.525 102 0.036 103 0.013 104 0.38 105 0.073 106 1.4107 2.379 108 >3 109 >3 110 >3 111 >3 112 >3 113 >3 114 0.51 115 >3 1160.025 117 0.002 118 0.695 119 0.008 120 0.02 121 0.016 122 0.025 1230.053 124 0.016 125 0.14 126 0.18 127 0.15 128 0.083 129 0.02 130 0.04131 0.155 132 >3 133 0.009 134 0.12 135 0.47 136 0.14 137 0.054 138 0.02139 0.033 140 0.068 141 0.22 142 1.7 143 >3 144 0.765 145 >3 146 0.017147 0.003 148 0.009 149 0.019 150 0.002 151 0.004 152 0.012 153 0.007154 0.988 155 0.505 156 0.73 157 0.408 158 (first 0.96 diastereomer) 158(second 0.395 diastereomer) 159 >3 160 >3 161 >3 162 163 >3 164 >3165 >3 166 >3 167 >3 168 (second 0.01 diastereomer) 168 (first 0.018diastereomer) 169 (first 0.011 diastereomer) 169 (second 0.021diastereomer) 170 0.23 171 0.009 172 0.05 173 1.3 174 >3 175 >3 176 0.49177 0.02 178 0.027 179 2 180 0.51 181 0.012 182 0.29 183 0.014 184 0.14185 0.011 186 0.11 187 0.49 188 0.024 189 0.17 190 1.5 191 0.002 1920.004 193 0.006 194 0.002 195 0.005 196 0.009 197 0.12 198 0.015 1990.021 200 0.085 201 0.53 202 0.006 203 0.14 204 0.17 205 1.1 206 0.36207 0.37 208 >3 209 0.008 210 0.28 211 >3 212 >3 213 >3 214 >3 215 0.57216 0.34 217 0.16 218 0.735 219 1.5 220 0.53 221 0.43 222 0.12 223 0.13224 0.006 225 1.5 226 0.14 227 0.61 228 >3 229 >3 230 >3 231 >3 232 1.5233 1.4 234 >3 235 1.4 236 0.17 237 0.093 238 0.695 239 0.072 240 0.57241 0.19 242 0.013 243 1.85 244 0.017 245 0.333 246 0.14 247 0.19 2480.027 249 2.933 250 >3 251 >3 252 >3 253 >3 254 >3 255 >3 256 >3 2570.008 258 >3 259 0.059 260 0.066 261 0.008 262 0.05 263 0.02 264 0.052265 0.035 266 0.0028 267 0.084 268 0.028 269 0.037 270 0.033 271 0.024272 0.089 273 0.059 274 0.0393 275 0.17 276 0.44 277 0.17 278 0.0036 2790.019 280 0.004 281 0.13 282 0.057 283 0.0042 284 0.004 285 0.026 2860.014 287 0.59 288 0.0203 289 0.039 290 0.0099 291 0.0128 292 0.0545 2930.0039 294 0.0068 295 0.0065 296 0.0246 297 0.074 298 0.0098 299 0.0064300 1.4 301 0.022 302 0.28 303 0.019 304 0.054 305 0.0023 306 0.019 3070.0059 308 0.036 309 0.0014 310 0.0025 311 0.013 312 0.0079 313 0.1213314 0.0065 315 0.12 316 0.024 317 0.52 318 0.0151 319 0.0052 320 0.0004321 0.011 322 0.0061 323 0.0008 324 0.0017 325 0.0016 326 0.0013 3270.0083 329 0.0127 330 0.029 331 0.0046 332 0.0027 333 0.0049 334 0.007335 0.0155 336 0.0056 337 0.0205 338 0.047 339 0.027 340 >3 341 0.33 3430.0048 344 0.0047 345 0.0025 346 0.0058 347 0.0031 348 0.02 349 >3350 >3 351 0.41 352 0.0018 353 0.0174 354 0.03 355 0.15 356 0.0033 3570.015  358* 0.075 359  360* 0.014  361* 0.044  362* 0.002  363* 0.003 364* 0.046 365 0.05  366* 0.013 367 0.33 368 0.005 369 0.009 370 0.043372 0.012 373 0.006 374 0.034 375 0.029 376 0.009 377 0.021 378 1.4 3790.022 380 0.026 381 0.016  382* 0.005 383 >3 1001  0.019 1002  0.031003  0.026 1004  0.029 1005  0.12 1006  >3 1007  0.17 1008  0.021 1009 0.17 1010  0.013 1011  0.47 1012  0.19 1013  0.013 1014  0.033 1015 0.36 1016  0.06 1017 (first 0.252 diastereomer) 1017 (second 0.017diastereomer) 1018  0.13 1019  0.079 1020  0.009 1021  0.041 1022  0.191023  0.1 1024  0.15 1025  0.002 1026  1027  >3 1028  0.59 1029  0.6951030  0.33 1031  2.05 1032 (first 0.524 diastereomer) 1032 (second 1.55diastereomer) 1033  0.84 1034  0.16 1035  0.017 1036  1.75 1037  >31038  0.17 1039  >3 1040  0.006 1041  0.038 *The indicated compoundswere analyzed in an E-VIPR assay conducted in the absence of humanserum. All other compounds were analyzed in an E-VIPR assay conducted inthe presence of human serum.

Many modifications and variations of the embodiments described hereinmay be made without departing from the scope, as is apparent to thoseskilled in the art. The specific embodiments described herein areoffered by way of example only.

What is claimed is:
 1. A compound of formula (I) or (II)

or a pharmaceutically acceptable salt thereof, wherein: each R isindependently H or C₁-C₆ alkyl; R_(3a) is H, halo, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; R_(4a) is H, halo, C₁-C₆alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; R_(1b) is H,halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy;R_(3b) is H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆haloalkoxy; R_(4b) is H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆alkoxy, or C₁-C₆ haloalkoxy; R₅, R₆, R₇, and R₈ are defined as follows:(i) R₅, R₆, and R₇ are each independently H, halo, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; and R₈ is C₁-C₆ alkyl;(ii) R₅ is W—(CH₂)_(n)—R_(z), C₁-C₆ alkylsulfanyl, —O—(CH₂)_(p)—R_(w),or —O—(CH₂)_(p)—N(C₁-C₆ alkyl)₂; R₆ and R₇ are each independently H,halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy;and R₈ is H; (iii) R₅ and R₆ are each independently H, halo, C₁-C₆alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; R₇ isW—(CH₂)_(n)—R_(z), —C≡C—R_(x), or 3-6 membered cycloalkyl or phenyl,wherein said 3-6 membered cycloalkyl or phenyl is substituted with 1-3substituents selected from a group consisting of C₁-C₆ alkoxy, CN, and—C(O)NH₂; and R₈ is H; or (iv) R_(s) is H, halo, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; R₆ and R₇, together withthe carbon atoms to which they are attached, form a ring of formula

and R₈ is H; R₉ is H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy,or C₁-C₆ haloalkoxy; R₁₀ is H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆alkoxy, or C₁-C₆ haloalkoxy; R₁₁ is H, halo, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; R₁₂ is H, halo, C₁-C₆alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; R₁₃ is H,halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy;each R₁₄ is independently H, halo, C₁-C₄ alkyl, or C₁-C₄ haloalkyl; eachW is independently O or a single bond; R_(x) is C₁-C₆ alkyl or 3-6membered cycloalkyl, wherein said 3-6 membered cycloalkyl may beunsubstituted or may be substituted with 1-3 substituents selected froma group consisting of halo, C₁-C₆ alkyl, and C₁-C₆ haloalkyl; each R_(w)is independently 3-6 membered cycloalkyl, phenyl, or 5-6 memberedheteroaryl, wherein said 3-6 membered cycloalkyl, phenyl, or 5-6membered heteroaryl may be unsubstituted or may be substituted with 1-3substituents selected from a group consisting of halo, C₁-C₆ alkyl, andC₁-C₆ haloalkyl; R_(z) is 3-6 membered heterocyclyl, 7-8 memberedcycloalkyl, or 4-8 membered cycloalkenyl, wherein said 3-6 memberedheterocyclyl, 7-8 membered cycloalkyl, or 4-8 membered cycloalkenyl maybe unsubstituted or may be substituted with 1-3 substituents selectedfrom a group consisting of halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, and C₁-C₆alkoxy, or wherein 2 substituents together with the atom to which theyare attached form a 5-6 membered heterocyclyl ring; n is 0 or 1; and pis 2 or
 3. 2. The compound of claim 1, wherein the compound has formula(I)

or a pharmaceutically acceptable salt thereof, wherein R, R_(3a),R_(4a), R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, and R₁₃ are as defined inclaim
 1. 3. The compound of claim 2, or a pharmaceutically acceptablesalt thereof, wherein R_(3a) and R_(4a) are each H.
 4. The compound ofclaim 1, wherein the compound has formula (II)

or a pharmaceutically acceptable salt thereof, wherein R, R_(1b),R_(3b), R_(4b), R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, and R₁₃ are asdefined in claim
 1. 5. The compound of claim 4, or a pharmaceuticallyacceptable salt thereof, wherein R_(1b), R_(3b), and R_(4b) are each H.6. The compound of any one of claims 1 to 5, or a pharmaceuticallyacceptable salt thereof, wherein each R is H.
 7. The compound of any oneof claims 1 to 6, or a pharmaceutically acceptable salt thereof, whereinR₅, R₆, and R₇ are each independently H, halo, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; and R₈ is C₁-C₆ alkyl. 8.The compound of any one of claims 1 to 6, or a pharmaceuticallyacceptable salt thereof, wherein R_(s) is H; R₆ is C₁-C₆ haloalkyl; R₇is H; and R₈ is C₁-C₆ alkyl.
 9. The compound of any one of claims 1 to6, or a pharmaceutically acceptable salt thereof, wherein In otherembodiments, R_(s) is H; R₆ is CF₃; R₇ is H; and R₈ is CH₃.
 10. Thecompound of any one of claims 1 to 6, or a pharmaceutically acceptablesalt thereof, wherein R₅ is W—(CH₂)_(n)—R_(z), C₁-C₆ alkylsulfanyl,—O—(CH₂)_(p)—R_(w), or —O—(CH₂)_(p)—N(C₁-C₆ alkyl)₂; R₆ and R₇ are eachindependently H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy; and R_(s) is H.
 11. The compound of any one of claims1 to 6, or a pharmaceutically acceptable salt thereof, wherein R₅ is

SCH₃,

or O(CH₂)₂N(CH₃)₂; R₆ is CF₃; R₇ is H; and R₈ is H.
 12. The compound ofany one of claims 1 to 6, or a pharmaceutically acceptable salt thereof,wherein R₅ and R₆ are each independently H, halo, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; R₇ is W—(CH₂)_(n)—R_(z),—C≡C—R_(x), or 3-6 membered cycloalkyl or phenyl, wherein said 3-6membered cycloalkyl or phenyl is substituted with 1-3 substituentsselected from a group consisting of C₁-C₆ alkoxy, CN, and —C(O)NH₂; andR₈ is H.
 13. The compound of any one of claims 1 to 6, or apharmaceutically acceptable salt thereof, wherein R₅ and R₆ are eachindependently H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy; R₇ is W—(CH₂)_(n)—R_(z); and R₈ is H.
 14. The compoundof any one of claims 1 to 6, or a pharmaceutically acceptable saltthereof, wherein R₅ and R₆ are each independently H, halo, C₁-C₆ alkyl,C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; R₇ is —C≡C—R_(x);and R₈ is H.
 15. The compound of any one of claims 1 to 6, or apharmaceutically acceptable salt thereof, wherein R₅ and R₆ are eachindependently H, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy; R₇ is 3-6 membered cycloalkyl or phenyl, wherein said3-6 membered cycloalkyl or phenyl is substituted with 1-3 substituentsselected from a group consisting of C₁-C₆ alkoxy, CN, and —C(O)NH₂; andR₈ is H.
 16. The compound of any one of claims 1 to 6, or apharmaceutically acceptable salt thereof, wherein R₅ is H, F, or CH₃; R₆is H; R₇ is

and R₈ is H.
 17. The compound of any one of claims 1 to 6, or apharmaceutically acceptable salt thereof, wherein R_(s) is H, halo,C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; R₆ andR₇, together with the carbon atoms to which they are attached, form aring of formula

and R₈ is H.
 18. The compound of any one of claims 1 to 6, or apharmaceutically acceptable salt thereof, wherein R₅ is H or F; R₆ andR₇, together with the carbon atoms to which they are attached, form aring of formula

and R₈ is H.
 19. The compound of any one of claims 1 to 18, or apharmaceutically acceptable salt thereof, wherein R₉ is C₁-C₆ alkoxy.20. The compound of any one of claims 1 to 18, or a pharmaceuticallyacceptable salt thereof, wherein R₉ is OCH₃, OC(¹H)₃, or OCD₃.
 21. Thecompound of any one of claims 1 to 20, or a pharmaceutically acceptablesalt thereof, wherein R₁₀ is H.
 22. The compound of any one of claims 1to 20, or a pharmaceutically acceptable salt thereof, wherein R₁₀ is F.23. The compound of any one of claims 1 to 22, or a pharmaceuticallyacceptable salt thereof, wherein R₁₁ is C₁-C₆ haloalkoxy.
 24. Thecompound of any one of claims 1 to 22, or a pharmaceutically acceptablesalt thereof, wherein R₁₁ is OCF₃.
 25. The compound of any one of claims1 to 24, or a pharmaceutically acceptable salt thereof, wherein R₁₂ isH.
 26. The compound of any one of claims 1 to 25, or a pharmaceuticallyacceptable salt thereof, wherein R₁₃ is H.
 27. A compound selected fromthe group of compounds identified in Table A, or a pharmaceuticallyacceptable salt thereof.
 28. A compound selected from the group ofcompounds identified in Table B, or a pharmaceutically acceptable saltthereof.
 29. The compound of claim 1, wherein the compound is selectedfrom the group of compounds identified in Table C, or a pharmaceuticallyacceptable salt thereof.
 30. The compound of claim 1, wherein thecompound is selected from the group of compounds identified in Table D,or a pharmaceutically acceptable salt thereof.
 31. The compound of anyone of claims 1-30.
 32. A pharmaceutical composition comprising atherapeutically effective amount of the compound of any one of claims1-30, or a pharmaceutically acceptable salt thereof, or the compound ofclaim 31 and one or more pharmaceutically acceptable carriers orvehicles.
 33. A pharmaceutical composition comprising the compound ofany one of claims 1-30, or a pharmaceutically acceptable salt thereof,or the compound of claim 31 and one or more pharmaceutically acceptablecarriers or vehicles.
 34. A method of inhibiting a voltage-gated sodiumchannel in a subject comprising administering to the subject thecompound of any one of claims 1-30, or a pharmaceutically acceptablesalt thereof, the compound of claim 31, or the pharmaceuticalcomposition of claim 32 or
 33. 35. The method of claim 34, wherein thevoltage-gated sodium channel is Na_(V)1.8.
 36. A method of treating orlessening the severity in a subject of chronic pain, gut pain,neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain,cancer pain, idiopathic pain, postsurgical pain, visceral pain, multiplesclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathologicalcough, or cardiac arrhythmia comprising administering to the subject aneffective amount of the compound of any one of claims 1-30, or apharmaceutically acceptable salt thereof, the compound of claim 31, orthe pharmaceutical composition of claim 32 or
 33. 37. The method ofclaim 36, where the method comprises treating or lessening the severityin the subject of neuropathic pain.
 38. The method of claim 37, whereinthe neuropathic pain comprises post-herpetic neuralgia.
 39. The methodof claim 37, wherein the neuropathic pain comprises small-fiberneuropathy.
 40. The method of claim 37, wherein the neuropathic paincomprises idiopathic small-fiber neuropathy.
 41. The method of claim 36,wherein the method comprises treating or lessening the severity in thesubject of musculoskeletal pain.
 42. The method of claim 41, wherein themusculoskeletal pain comprises osteoarthritis pain.
 43. The method ofclaim 36, wherein the method comprises treating or lessening theseverity in the subject of acute pain.
 44. The method of claim 43,wherein the acute pain comprises acute post-operative pain.
 45. Themethod of claim 36, wherein the method comprises treating or lesseningthe severity in the subject of postsurgical pain.
 46. The method ofclaim 45, wherein the postsurgical pain comprises bunionectomy pain. 47.The method of claim 45, wherein the postsurgical pain comprisesabdominoplasty pain.
 48. The method of claim 45, wherein thepostsurgical pain comprises herniorrhaphy pain.
 49. The method of claim36, wherein the method comprises treating or lessening the severity inthe subject of visceral pain.
 50. The method of any one of claims 34-49,wherein said subject is treated with one or more additional therapeuticagents administered concurrently with, prior to, or subsequent totreatment with the compound, pharmaceutically acceptable salt, orpharmaceutical composition.
 51. The compound of any one of claims 1-30,or a pharmaceutically acceptable salt thereof, the compound of claim 31,or the pharmaceutical composition of claim 32 or 33 for use as amedicament.